Topical corticosteroids for the treatment of inflammatory diseases of the gastrointestinal tract

ABSTRACT

Provided herein are methods for preventing or alleviating the symptoms of and inflammation associated with inflammatory diseases and conditions of the gastrointestinal tract, for example, those involving the esophagus. Also provided herein are pharmaceutical compositions useful for the methods of the present invention.

CROSS-REFERENCE

This application is a continuation of Ser. No. 12/269,572, filed Nov.12, 2008 entitled “Topical Corticosteroids for the Treatment ofInflammatory Diseases of the Gastrointestinal Tract”, now U.S. Pat. No.8,679,545, which is a continuation-in-part application of Ser. No.11/595,513, filed Nov. 9, 2006, published as US 2007/0111978 on May 17,2007, and entitled “Viscous Budesonide for the Treatment of InflammatoryDiseases of the Gastrointestinal Tract”, now U.S. Pat. No. 8,324,192,which is incorporated herein by reference in its entirety and to whichapplication we claim priority under 35 USC §120, which claims priorityto U.S. Provisional Application Ser. No. U.S. 60/735,340, filed Nov. 12,2005, and entitled “Viscous Budesonide for the Treatment of InflammatoryDiseases of the Gastrointestinal Tract” which is referred to andincorporated herein by reference in its entirety.

This application also claims the benefit of U.S. Provisional ApplicationNo. 61/090,572, filed Aug. 20, 2008, which application is incorporatedherein by reference.

FIELD OF THE INVENTION

The invention is in general directed to methods and pharmaceuticalcompositions for preventing or alleviating the symptoms of andinflammation associated with inflammatory diseases involving theesophagus.

BACKGROUND OF THE INVENTION

Esophageal inflammation disorders are gaining increased recognition inboth adults and children. One example is eosinophilic esophagitis (EE orEoE), which is an emerging, and fast-growing disorder characterized byhigh levels of eosinophils in the esophagus, as well as basal zonehyperplasia. EE is thought to be provoked, in at least a subset ofpatients, by food allergies or airborne allergen exposure (1-5, 44). EEdiagnosis is often associated with other hypersensitivity disorders,including asthma, rhinitis, and other food and aeroallergen inhalantsensitivities (39-40). Diagnosis is often made, e.g., in young childrenand depends on the finding of 15 to 20 or more to 24 or more eosinophilsper high power field (eos/hpf) within esophageal mucosal biopsies(6-12).

In parallel with other atopic disorders, the incidence of EE appears tobe increasing (15, 35). The disorder may present with reflux-likesymptoms, pain and dysphagia, clinical symptoms similar to thepresentation of gastroesophageal reflux disease (“GERD”) (42). Symptomsof EE may include, for example, one or more of the following: abdominalpain, chest pain, choking, difficulty swallowing, failure to thrive,nausea, reflux not relieved by standard anti-flux therapy, skin rash orhives, vomiting, and weight loss. In one series, 15% of EE patients hadconcurrent developmental delay (45).

Although EE is becoming more frequently diagnosed throughout developingcountries (7, 8, 13-16) many aspects of the disease remain unclearincluding its etiology, natural history and optimal therapy. Symptoms ofEE often mimic those of GERD and include vomiting, dysphagia, pain andfood impaction (8, 14, 17-20). However, treatment of EE and GERD differand it is important to distinguish between them, particularly asuntreated EE may be associated with esophageal narrowing in 10-30% ofcases (14, 18, 20, 21). The common occurrence regarding misdiagnosis ofEE for GERD often results in delayed treatment for patients with EE.(42).

Long term systemic steroid therapy can result in significant secondaryside effects on growth and bone development, therefore topical steroidformulations are often used to treat EE and potentially otherinflammatory gastrointestinal diseases and conditions involving theesophagus. Although treatment with anti-IL-5 monoclonal antibody hasbeen reported to be successful in EE, this therapy is currently notapproved for use in children (36).

Current treatments include elimination diets (22, 23), and elementalformulas (2, 24). Identifying true inciting food allergens can bedifficult and elemental formulas are often unpalatable, thereby makingdietary interventions complicated (1, 22). Systemic corticosteroids andswallowed topical steroids, such as fluticasone proprionate (Flovent™)administered through metered-dose inhaler (MDI), have been shown toinduce and maintain low esophageal eosinophil levels (25-30). In onemethod, for example, a fluticasone metered dose inhaler (MDI) is puffedinto the oropharynx and swallowed (26). Improvised puff and swallowtechniques may be difficult for patients, especially smaller children,and especially children with developmental delays, to performefficiently. This may result in a less than effective dose of a topicalsteroid being delivered to the esophagus.

SUMMARY OF THE INVENTION

Provided herein are methods for preventing and alleviating any chronicinflammatory or malignant state that involves the esophagus and respondsto steroid therapy. The methods of the present invention are useful, forexample, for preventing and alleviating the symptoms and inflammation ofeosinophilic esophagitis, inflammatory bowel diseases involving theesophagus, Crohn's disease, esophageal inflammation secondary tocaustic/irritant ingestion, persistent/recurrent esophageal stricturesof any cause and including caustic/irritant ingestion, pill-inducedesophagitis, systemic diseases, congenital diseases, Epidermolysisbullosa, and post-surgery inflammation. The present methods are alsouseful for preventing or alleviating symptoms and inflammationassociated with other diseases or conditions of the gastrointestinaltract, for example, the upper gastrointestinal tract, where it isbeneficial to target a particular target site, rather than providesystemic therapy. Also provided herein are pharmaceutical compositionsuseful in the methods of the present application.

Thus, in one embodiment is provided a method of preventing oralleviating esophageal inflammation in an individual comprising orallyadministering to said individual a corticosteroid in association with atleast one excipient to increase the viscosity of the composition. Incertain embodiments, the viscosity of the composition is about that of asuspension prepared by adding about 5 to about 15 grams of sucralose(Splenda®, Distributed By: McNeil Nutritionals, LLC, Fort Washington,Pa. 19034-2299) to 4 ml of water, or about 10 to about 12 grams ofsucralose (Splenda®) to 4 ml of water, wherein the viscosity is measuredat 25 degrees Celsius. In certain aspects, the corticosteroid is atopical corticosteroid, such as, for example, Budesonide. In someembodiments, the individual has eosinophilic esophagitis. The individualmay, for example, have been diagnosed with a disease or conditionselected from the group consisting of eosinophilic esophagitis,inflammatory bowel diseases involving the esophagus, Crohn's disease,esophageal inflammation secondary to caustic/irritant ingestion,persistent/recurrent esophageal strictures of any cause and includingcaustic/irritant ingestion, pill-induced esophagitis, systemic diseases,congenital diseases, and post-surgery inflammation.

Although the methods of the invention may be used to prevent oralleviate esophageal inflammation in a mammal, for example a human, ofany age, in certain examples, the individual is a child, for example, achild less than 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1years old.

Also provided in the present invention is a pharmaceutical compositioncomprising a corticosteroid and a viscosity-increasing excipient, forexample, a topical corticosteroid, such as, for example, Budesonide. Thepharmaceutical composition may be, for example, in liquid form. Alsoprovided are pharmaceutical compositions comprising a corticosteroid,for example a topical corticosteroid, such as, for example, Budesonide,in the form of a dissolving tablet, a dissolving wafer, a capsule, or agel capsule. In certain embodiments, these tablets, wafers, and capsulesare formulated with at least one excipient to deliver a viscous form ofthe corticosteroid to the esophagus.

The excipient may be, for example, selected from the group consisting oflactose, sucrose, sucralose (Splenda®, Distributed By: McNeilNutritionals, LLC, Fort Washington, Pa. 19034-2299), mannitol, sorbitol,honey, maize starch, wheat starch, rice starch, potato starch, gelatin,gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodiumcarboxymethyl-cellulose (CMC), and polyvinylpyrrolidone (PVP: povidone).The excipient may be, for example, selected from the group consisting oflactose, sucrose, sucralose (Splenda®), mannitol, sorbitol, honey, maizestarch, wheat starch, rice starch, potato starch, gelatin, gumtragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodiumcarboxymethyl-cellulose (CMC), and polyvinylpyrrolidone (PVP: povidone).In certain illustrative examples, the excipient is sucralose (Splenda®).

The pharmaceutical composition in certain embodiments comprises atherapeutically effective amount of corticosteroid to prevent oralleviate esophageal inflammation. In certain embodiments, 1-2 mg or 2-3mg or corticosteroid per day is administered to said individual.

Provided in some embodiments herein is an oral pharmaceuticalcomposition comprising a corticosteroid, a vehicle and a coating agent.In some embodiments, the coating agent is a mucoadhesive agent. Inspecific embodiments, the mucoadhesive agent is selected from carbopol,alginate, maltodextrin, or a combination thereof. In certainembodiments, the mucoadhesive agent imparts an increased viscosity uponthe oral pharmaceutical composition. In further or alternativeembodiments, the oral pharmaceutical composition comprising amucoadhesive agent further comprises a viscosity enhancing agent. Insome embodiments, the coating agent is maltodextrin. In someembodiments, the composition is thixotropic. In certain embodiments, thecorticosteroid is a topically active corticosteroid. In specificembodiments, the topically active corticosteroid is budesonide. In someembodiments, the vehicle is a liquid vehicle. In certain embodiments,the composition has a total volume of about 2 mL to about 20 mL. In someembodiments, the oral pharmaceutical composition further comprises asweetener, an antioxidant, a surfactant, a buffering agent, or acombination thereof.

Provided in some embodiments herein is an oral pharmaceuticalcomposition comprising a corticosteroid, a vehicle and maltodextrin. Insome embodiments, the vehicle is a liquid vehicle. In certainembodiments, the composition comprises about 0.1 g of maltodextrin permL of liquid vehicle to about 0.6 g of maltodextrin per mL of liquidvehicle.

In certain embodiments, provided herein is a method of treating,preventing or alleviating gastrointestinal inflammation or symptoms ofgastrointestinal inflammation in an individual comprising orallyadministering to said individual a pharmaceutical composition comprisinga corticosteroid, a liquid vehicle and a coating agent. In someembodiments, the esophageal inflammation is eosinophilic esophagitis, aninflammatory bowel disease involving the esophagus, Crohn's disease,esophageal inflammation secondary to caustic/irritant ingestion,persistent/recurrent esophageal strictures of any cause and includingcaustic/irritant ingestion, pill-induced esophagitis, systemic diseases,congenital diseases, post-surgery inflammation, or a combinationthereof. In specific embodiments, the esophageal inflammation iseosinophilic esophagitis. In some embodiments, about 0.25 mg to about 10mg corticosteroid per day is administered to the individual receivingtreatment. In certain embodiments, the corticosteroid composition isadministered once a day, or no more than once a day.

In some embodiments, provided herein is a method of treating allergicinflammation of the gastrointestinal tract in an individual comprisingcoating an inflamed portion of the gastrointestinal tract of anindividual with an effective amount of a pharmaceutical composition,wherein the pharmaceutical composition comprises a topically activecorticosteroid. In certain embodiments, the administered pharmaceuticalcomposition comprises a coating agent. In some embodiments, the coatingagent is a viscosity enhancing agent, a mucoadhesive agent, or acombination thereof. In certain embodiments, the effective amount of thepharmaceutical composition is about 2 mL to about 20 mL.

In some embodiments, oral administration of a pharmaceutical compositiondescribed herein provides a decreased systemic load of corticosteroid,as measured by plasma AUC_(0-∞), when compared to inhaled administrationdelivering an identical amount of corticosteroid.

In certain embodiments, provided herein is a method of treating allergicor caustic esophageal inflammation in an individual comprising orallyadministering a corticosteroid to an individual in need thereof anddelivering the corticosteroid along the entire length of the esophagus.In some embodiments, the corticosteroid is administered in combinationwith a coating agent. In certain embodiments, the coating agent is aviscosity enhancing agent, a mucoadhesive agent, or a combinationthereof. In some embodiments, the administered corticosteroid is in theform of a microparticle. In specific embodiments, at least 95% of themicroparticles have a diameter of less than 10 microns. In further oralternative embodiments, the corticosteroid microparticle is suspendedin a liquid vehicle.

BRIEF DESCRIPTION OF THE DRAWINGS

The novel features of the invention are set forth with particularity inthe appended claims. A better understanding of the features andadvantages of the present invention will be obtained by reference to thefollowing detailed description that sets forth illustrative embodiments,in which the principles of the invention are utilized, and theaccompanying drawings of which:

FIG. 1: Pretreatment distal esophageal biopsy showing marked basal zonehyperplasia (white arrow), numerous intraepithelial eosinophils (blackarrow) with a few degranulated eosinophils, intercellular edema andfibrosis of the lamina propria (Hematoxylin & eosin, originalmagnification×125; inset×500). Basal zone hyperplasia is reported whenbasal zone cells extend towards the luminal surface of the epithelium(>25% of epithelial thickness).

FIG. 2: Post-treatment distal esophageal biopsy showing normalization.Note absence of eosinophils and intercellular edema (Hematoxylin &eosin, original magnification×125, inset×500).

FIG. 3: Distal esophageal image of patient with eosinophilic esophagitis(Olympus P160 endoscope) showing pallor, lichenification of the mucosawith linear furrowing (arrow). Following treatment with viscousbudesonide, the esophagus appears normal (lower).

FIG. 4: Illustrates the reduced systemic affect of swallowing an oralcomposition described herein when compared to the administration of aninhaled corticosteroid composition.

FIG. 5: Illustrates the increased interaction between a viscouscomposition described herein and the esophagus when compared to anon-viscous composition.

DETAILED DESCRIPTION OF THE INVENTION

Abbreviations: EE or EoE: Eosinophilic Esophagitis; MDI: Metered DoseInhaler; hpf: high powered field; eos: eosinophil.

Provided herein are methods and pharmaceutical compositions forpreventing or alleviating the symptoms of and inflammation associatedwith inflammatory diseases involving the esophagus.

In certain embodiments, the present invention is directed to methods andpharmaceutical compositions for treating, preventing or alleviating thesymptoms of and allergic or caustic inflammation associated withinflammatory disorders involving the gastrointestinal tract, includingthe esophagus. Provided herein are methods of treating, preventing oralleviating, for example, allergic or caustic esophageal inflammation inan individual. In some embodiments, provided herein is a method fortreating, preventing or alleviating the symptoms of and inflammationassociated with allergic or caustic inflammatory disorders involving thegastrointestinal tract, including the esophagus, by topicallyadministering a corticosteroid to the gastrointestinal tract (e.g.,esophagus). In specific embodiments, the corticosteroid is administeredin a composition that coats a surface of the gastrointestinal tract(e.g., the esophagus). In some embodiments, the corticosteroid isadministered along the length of (e.g., the entire length of) anafflicted surface of the gastrointestinal tract (e.g., the esophagus).In some embodiments, the corticosteroid is in a composition inassociation with at least one excipient to increase the ability of thecomposition to coat the surface of the gastrointestinal tract or aportion of the gastrointestinal tract (e.g., the esophagus). As usedherein, an excipient that increases the ability of the composition tocoat the surface of the gastrointestinal tract or portion thereof isused interchangeably with a coating agent. In certain instances, coatingagents allow for an increased residence time of the composition on thesurface of the gastrointestinal tract, or a portion thereof (e.g.,esophagus). In some embodiments, the excipient that increases theability of the composition to coat the gastrointestinal tract or portionthereof is an excipient that increases the mucoadhesive characteristicof the composition (i.e., can be a mucoadhesive agent), increases theviscosity of the composition (i.e., can be a viscosity increasingagent), or a combination thereof. In some embodiments, provided hereinis a pharmaceutical composition comprising a corticosteroid and amucoadhesive agent. In certain embodiments, a pharmaceutical compositiondescribed herein further comprises a liquid vehicle. In further oralternative embodiments, the pharmaceutical composition is suitable fororal administration. In some embodiments, the increased coating abilityand/or mucoadhesive characteristic of the composition allows thecomposition to be in contact with a surface of the gastrointestinaltract (e.g., the surface of the esophagus) for an extended period oftime following administration. As used herein, mucoadhesive agents areagents that increase the interaction of a composition or active withinthe composition with a surface of the gastrointestinal tract (e.g., themucosa and/or epithelium of the gastrointestinal tract or of a specificsite of the gastrointestinal tract, such as the esophagus).

An increase in the interaction of the composition with the surface ofthe gastrointestinal tract (e.g., esophagus) may be measured bymeasuring the retention time of the material along a length of agastrointestinal surface, wherein the retention time is increased in thepresence of the excipients as compared to its absence. As used herein,in certain embodiments, a gastrointestinal surface includes agastrointestinal mucosa and/or a gastrointestinal epithelium, all ofwhich terms are used interchangeably herein. In another embodiment, anincreased interaction may be measured by the decrease in physiologicalmanifestations or symptoms of the disease or ailment to be treated,including a decrease in total eosinophil counts in a sample collectedfrom the surface tissue of the gastrointestinal tract (e.g., esophagus).

In one aspect of the invention, the use of the excipients may act todecrease the quantity of active agents needed to elicit a response inthe absence of the excipients. In some embodiments, the excipients maydecrease the amount of corticosteroid used, for example, from about 1 toabout 3 mg of budesonide in the absence of an excipient to about 250 μgto about 2 mg of budesonide in the presence thereof. Accordingly, thecompositions provided herein may provide an additional advantage ofdecreasing the amount of active agent needed to treat subjects afflictedby allergic or caustic inflammation of the gastrointestinal tract,including the esophagus.

It has been found that by administering Budesonide in oral form, in aformulation with increased fluid viscosity, that the corticosteroid wasdelivered to the esophagus in an effective dose to reduce theinflammation of the esophagus. In the treatment of more than 40patients, this treatment was found to be effective in targetinginflammation within the esophagus. Specific examples of two patients,both children, are presented in Examples 1 and 2. A viscous oralsuspension of budesonide improved symptoms, resolved endoscopicabnormalities, and markedly reduced or eliminated esophageal eosinophilsin two patients unable to utilize a metered dose inhaler with puff andswallow technique. Although this therapy is particularly beneficial tochildren in that they often have the most difficulty using the puff andswallow technique, the methods of the present invention may also be usedfor individuals of any age. By “individual” is meant any animal, forexample, a mammal, or, for example, a human, including, for example,patients in need of treatment.

Diseases

Provided herein are methods and pharmaceutical compositions fortreating, preventing or alleviating the symptoms of, and inflammationassociated with, caustic or allergic inflammatory disorders of thegastrointestinal tract, including but not limited to the uppergastrointestinal tract (e.g., the esophagus).

In certain embodiments, a corticosteroid (e.g., budesonide) that isadministered in oral form, in a formulation with increased coating(e.g., viscosity and/or mucoadhesive) characteristic, is delivered to,e.g., the esophagus in an effective dose to reduce the inflammation ofthe esophagus.

Diseases or conditions that may be treated, prevented, or exhibit analleviation of symptoms according to the present invention include anydisease or condition that involves esophageal inflammation. Thisincludes, for example, any chronic inflammatory or malignant state thatinvolves the esophagus and responds to steroid therapy. The methods ofthe present invention are useful, for example, for preventing andalleviating the symptoms of eosinophilic esophagitis, inflammatory boweldiseases involving the esophagus, Crohn's disease, acute esophagealinflammation secondary to caustic/irritant ingestion,persistent/recurrent esophageal strictures secondary tocaustic/irritant, conditions due to ingestion, systemic diseases,congenital diseases, and post-surgery inflammation.

An individual suitable for treatment with the compositions disclosedherein may, for example, have been diagnosed with a disease or conditionincluding, but not limited to, eosinophilic esophagitis, inflammatorybowel diseases involving the esophagus, Crohn's disease, esophagealinflammation secondary to caustic/irritant ingestion,persistent/recurrent esophageal strictures of any cause and includingcaustic/irritant ingestion, pill-induced esophagitis, systemic diseases,congenital diseases, or post-surgery inflammation. In certainembodiments, these methods comprise orally administering to saidindividual a corticosteroid-containing compositions described herein.

In certain embodiments, provided herein is a method of treating,preventing or alleviating allergic or caustic inflammation of thegastrointestinal tract, including, by way of non-limiting example, theesophagus, in an individual comprising orally administering to saidindividual any of the compositions described herein. In certainembodiments, the oral dosage form comprises a liquid vehicle and isformulated as, e.g., a slurry, suspension, syrup, solution, dispersion,etc.

In one aspect, a patient is administered a corticosteroid such as, forexample, budesonide.

In some embodiments, the inflammation treated by the methods andcompositions described herein is associated with eosinophilicinflammation. In some embodiments, individuals (e.g., patients) to betreated with compositions described herein include those that have beendiagnosed with eosinophilic esophagitis, an inflammatory bowel diseaseinvolving the esophagus, Crohn's disease, esophageal inflammationsecondary to caustic/irritant ingestion, persistent/recurrent esophagealstrictures of any cause and including caustic/irritant ingestion,pill-induced esophagitis, systemic diseases, congenital diseases, orpost-surgery inflammation. In one non-limiting example, the patient haseosinophilic esophagitis. In some embodiments, the patient is an adult.In other embodiments, the patient is a child or infant. In variousaspects, a patient is a child or infant less than 19 years old, lessthan 16 years old, less than 12 years old, less than 8 years old, lessthan 6 years old, less than 4 years old, less than 2 years old, 2-18years old, or 2-19 years old.

In some embodiments, a composition is in a unit dose formulation fororal administration to a patient. In some embodiments, a unit dose ofthe corticosteroid is administered from a metered dose device. In someembodiments, the metered dose device delivers a metered unit dose of acomposition described herein to the mouth or throat of an individual inneed thereof. In certain embodiments, the metered dose device is ametered inhaler, which is utilized to administer a metered unit dose tothe mouth or throat of an individual (the individual swallows ratherthan inhales the metered unit dose). In some embodiments, a compositionor unit dose described herein is administered as a nebulizedcomposition, an aerosolized composition, an emulsion, a solution, asuspension, a syrup, a slurry, a dispersion, a colloid, a dissolvingtablet, a dissolving wafer, a capsule, a gel capsule, a semi-solid, asolid forma gel, a gel matrix, a cream, a paste, or the like. In certainaspects, about 0.01 mg to about 20 mg, about 0.01 mg to about 15 mg, orabout 0.01 mg to about 10 mg (e.g., about 0.1-10 mg, about 0.25-5 mg,about 0.25-2.5 mg, about 1-2 mg or about 2-3 mg, about 0.25 mg to about6 mg, about 0.5 mg to about 6 mg corticosteroid, about 0.5 mg to about 2mg of corticosteroid, about 1 mg to about 2 mg of corticosteroid, about2 mg to about 3 mg of corticosteroid, about 3 mg to about 4 mg ofcorticosteroid, about 4 mg to about 5 mg of corticosteroid, or about 5mg to about 6 mg) of corticosteroid per day or per dose is administeredto an individual. In some embodiments, the corticosteroid is present ina composition or a unit dose of a composition described herein in anamount of from about 0.01 mg to about 10 mg (e.g., about 0.1-10 mg,about 0.25-5 mg, about 0.25-2.5 mg, about 1-2 mg or about 2-3 mg, about0.5 mg to about 2 mg, about 1 to about 2 mg, about 1 mg, or about 2 mg).In some embodiments, the amount of corticosteroid administered daily orin a unit dose is between about 0.5 mg and about 3 mg, between about 0.5mg and about 4 mg, or between about 0.35 mg and about 4 mg. In otherembodiments, the amount of corticosteroid present in a unit dose oradministered daily is between about 1 and about 3 mg, or between about 1and about 2 mg, or between about 2 and about 3 mg.

In certain aspects, about 0.05 mg to about 50 mg, about 0.25 mg to about20 mg, about 0.25 mg to about 15 mg, about 0.25 mg to about 10 mg, orabout 0.25 mg to about 5 mg (e.g., about 0.1 to about 5 mg, about 0.25to about 2.5 mg, about 0.3 mg to about 2 mg, about 0.5 mg to about 1 mg,about 0.7 mg to about 1.5 mg, about 0.375 mg, about 0.75 mg, about 1 mg,about 1.25 mg, about 1.5 mg or about 2 mg) corticosteroid per day or perdose is administered to a patient. In some embodiments, thecorticosteroid is present in a unit dose in an amount of between about0.25 mg and about 5 mg. In some embodiments, the amount ofcorticosteroid administered daily or in a unit dose is between about 0.5mg and about 3 mg. In other embodiments, the amount of corticosteroidpresent in a unit dose or administered daily is between about 1 andabout 3 mg, or between about 1 and about 2 mg, between about 0.5 mg andabout 4 mg, between about 0.35 mg and about 4 mg, or between about 2 andabout 3 mg.

Provided in certain embodiments herein is a method of treating allergicor caustic inflammation of the gastrointestinal tract (e.g., of theesophagus) in an individual comprising coating an inflamed portion ofthe gastrointestinal tract (e.g., a portion or a substantial portion ofthe esophagus) of an individual with an effective amount of apharmaceutical composition. In specific embodiments, the pharmaceuticalcomposition comprising a therapeutically effective amount of a topicallyactive corticosteroid. In certain embodiments, the pharmaceuticalcomposition further comprises a coating agent (e.g., a mucoadhesiveagent and/or a viscosity enhancing agent). In some embodiments, theinflamed portion of the gastrointestinal portion is at least partiallycoated, or substantially coated. In certain embodiments, the effectiveamount of the pharmaceutical composition is an amount sufficient to coatthe esophagus (e.g., a volume as set forth herein). In certainembodiments, the allergic or caustic inflammation of thegastrointestinal tract is the esophagus and the composition at leastpartially coats the esophagus (including all or part of the inflamedportions of the esophagus). In specific embodiments, the inflammation ofthe gastrointestinal tract is allergic inflammation of the esophagus(e.g., eosinophilic esophagitis).

The present methods are also useful for treating, preventing oralleviating symptoms and/or inflammation associated with other diseasesor conditions of the gastrointestinal tract, for example, the uppergastrointestinal tract, where it is beneficial to target a particulartarget site, rather than provide systemic therapy. Also provided hereinare pharmaceutical compositions useful in the methods of the presentapplication. As used herein, inflammation and/or symptoms associatedwith a disorder or disease disclosed herein includes inflammation and/orsymptoms associated with, caused by and/or resulting from the disorderor disease.

In certain embodiments, provided herein is a method of treating allergicor caustic gastrointestinal inflammation in an individual comprisingorally administering a pharmaceutical composition to an individual inneed thereof and delivering the pharmaceutical composition to aninflamed portion of the gastrointestinal tract, wherein thepharmaceutical composition comprises a topically active corticosteroid.In further embodiments, upon delivery of the pharmaceutical compositionto the inflamed portion of the gastrointestinal tract, thepharmaceutical composition coats the inflamed portion of thegastrointestinal tract. In further embodiments, coating of the inflamedportion of the gastrointestinal tract provides prolonged exposure of theinflamed portion of the gastrointestinal tract to the pharmaceuticalcomposition. In still further embodiments, prolonged exposure of theinflamed portion of the gastrointestinal tract to the pharmaceuticalcomposition provides increased local delivery of the corticosteroid. Insome embodiments, increased local delivery of the corticosteroid to asurface of the gastrointestinal tract decreases undesired systemicabsorption of the corticosteroid. In some embodiments, the inflamedportion of the gastrointestinal portion is at least partially coated, orsubstantially coated. In certain embodiments, the effective amount ofthe pharmaceutical composition is an amount sufficient to coat theesophagus (e.g., a volume as set forth herein). In certain embodiments,the allergic or caustic inflammation of the gastrointestinal tract isthe esophagus and the composition at least partially coats the esophagus(including all or part of the inflamed portions of the esophagus). Inspecific embodiments, the inflammation of the gastrointestinal tract isallergic inflammation of the esophagus (e.g., eosinophilic esophagitis).

In some embodiments, provided herein is a method of reducing systemicexposure to a corticosteroid in an individual being treated for allergicor caustic gastrointestinal inflammation, the method comprising orallyadministering a pharmaceutical composition and coating an inflamedportion of the gastrointestinal tract with the pharmaceuticalcomposition, wherein the pharmaceutical composition comprises acorticosteroid. In certain embodiments, systemic exposure to thecorticosteroid is reduced by using a topical, locally actingcorticosteroid, instead of a systemically acting corticosteroid for thetreatment of allergic or caustic gastrointestinal inflammation. In someembodiments, the topical, local delivery of the pharmaceuticalcomposition does not provide substantial systemic exposure. In someembodiments, the inflamed portion of the gastrointestinal portion is atleast partially coated, or substantially coated with the pharmaceuticalcomposition. In certain embodiments, the effective amount of thepharmaceutical composition is an amount sufficient to coat the esophagus(e.g., a volume as set forth herein). In certain embodiments, theallergic or caustic inflammation of the gastrointestinal tract is theesophagus and the composition at least partially coats the esophagus(including all or part of the inflamed portions of the esophagus). Inspecific embodiments, the inflammation of the gastrointestinal tract isallergic inflammation of the esophagus (e.g., eosinophilic esophagitis).

In certain embodiments, provided herein is a method of orallyadministering a composition comprising a corticosteroid wherein systemicexposure of corticosteroid is reduced (e.g., significantly reduced)compared to the pulmonary administration of a nebulized or aerosolizedcorticosteroid composition with the same nominal or delivered dose. Insome embodiments, provided herein is a method of orally administering(e.g., by drinking or swallowing) a composition comprising acorticosteroid wherein systemic exposure of corticosteroid is reduced(e.g., significantly reduced) compared to the oral administration of anebulized or aerosolized corticosteroid composition (which is sprayed onthe targeted site of the gastrointestinal site, e.g., esophagus)comprising a corticosteroid.

It will be appreciated by those skilled in the art that reference hereinto treatment extends to prophylaxis as well as the treatment ofinflammation or other symptoms.

Compounds

In certain embodiments, the corticosteroids used in the presentinvention include topical steroids including, for example, budesonide.In some embodiments, corticosteroids are selected from, by way ofnon-limiting example, aclometasone, amcinomide, beclometasone,betamethasone, budesonide, ciclesonide, clobetasol, clobetasone,clocortolone, cloprednol, cortivazol, deflazacort, deoxycorticosterone,desonide desoximetasone, dexamethasone, diflorasone, diflucortolone,difluprednate, fluclorolone, fludrocortisone, fludroxycortide,flumetasone, flunisolide, fluocinolone acetonide, fluocinonide,fluocortin, fluocortolone, fluorometholone, fluperolone, fluticasone,fluticasone propionate, fuprednidene, formocortal, halcinonide,halometasone, hydrocortisone aceponate, hydrocortisone buteprate,hydrocortisone butyrate, loteprednol, medrysone, meprednisone,methylprednisolone, methylprednisolone aceponate, mometasone furoate,paramethasone, prednicarbate, prednisone, prednisolone, prednylidene,remexolone, tixocortol, triamcinolone and ulobetasol, and combinations,pharmaceutically acceptable salts and esters thereof.

In certain embodiments, the corticosteroid(s) utilized herein areutilized as particles (e.g., corticosteroid particles suspended ordispersed in an aqueous medium). In specific embodiments, the particlesare microparticles. In some embodiments, the microparticles have a meandiameter of about 0.1 microns to about 50 microns. In specificembodiments, the microparticles have a mean diameter of about 1 micronto about 20 microns. In certain embodiments, at least 95%, at least 98%,or at least 99% of the microparticles have a diameter of less than 10microns.

Formulation

While the compositions of the present invention will typically be usedin therapy for human patients, they may also be used in veterinarymedicine to treat similar or identical diseases. The compositions may,for example, be used to treat mammals, including, but not limited to,primates and domesticated mammals. The compositions may, for example beused to treat herbivores. The compositions of the present inventioninclude geometric and optical isomers.

Pharmaceutical compositions suitable for use in the present inventioninclude compositions wherein the active ingredients are contained in aneffective amount to achieve its intended purpose. Determination of theeffective amounts is well within the capability of those skilled in theart, especially in light of the detailed disclosure provided herein.

Liquid suspensions of the present invention include, for example, thoseprepared by adding about 5 to about 25 grams of sucralose (Splenda®,Distributed By: McNeil Nutritionals, LLC, Fort Washington, Pa.19034-2299), or about 7 to about 20 grams of sucralose (Splenda®), orabout 5 to about 15 grams of sucralose (Splenda®), or about or about 7to about 15 grams of sucralose (Splenda®), or about 8 to about 12 gramsof sucralose (Splenda®), or about 10 to about 11 grams of sucralose(Splenda®), or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, 24, or 25 grams of sucralose (Splenda®),added to 2 mL or 4 mL of Budesonide, such as that obtained from aBudesonide respule, or larger or smaller volumes having the same ratiosof sucralose (Splenda®) to Budesonide. Smaller or larger volumes offormulations provided herein may also be used. In some embodiments, thevolume used in a formulation provided herein comprises components in theratios as described above.

The exact dosage will depend upon the route of administration, the formin which the composition is administered, the subject to be treated, theage, body weight/height of the subject to be treated, and the preferenceand experience of the attending physician. In certain embodiments, theoptimal concentration of the corticosteroid in the composition dependsupon the specific corticosteroid used, the characteristics of thepatient, and the nature of the inflammation for which the treatment issought. In various embodiments, these factors are determined by those ofskill in the medical and pharmaceutical arts in view of the presentdisclosure.

Generally, a therapeutically effective dose is desired. Atherapeutically effective dose refers to the amount of thecorticosteroid that results in a degree of amelioration of symptomsand/or inflammation relative to the status of such symptoms and/orinflammation prior to treatment. The dosage forms and methods ofapplying dosage forms containing effective amounts are within the scopeof the instant invention. In various embodiments, the amount ofcorticosteroid (e.g., budesonide) used in a method or in a compositiondescribed herein is from about 10 to 400 μg/kg of body weight per day,or for example, in the range of 20 to 300 μg/kg per day, or for examplein the range of 30 to 200 μg/kg per day, or for example in the range of30 to 100 μg/kg per day, or for example in the range of 35 to 100 μg/kgper day, or for example in the range of 40 to 100 μg/kg per day, or forexample in the range of 35 to 60 μg/kg per day, or for example in therange of 10-50 μg/kg per day, or for example in the range of 10-100μg/kg/day, or for example in the range of 30-50 μg/kg/day, or in anillustrative embodiment in the range of 40-60 μg/kg/day, about 2.5 to400 μg/kg of body weight per day, or for example, in the range of 5 to300 μg/kg per day, or for example in the range of 5 to 200 μg/kg perday, or for example in the range of 5 to 100 μg/kg per day, or forexample in the range of 10 to 100 μg/kg per day, or for example in therange of 5-50 μg/kg/day, or in an illustrative embodiment in the rangeof 10-60 μg/kg/day or in an illustrative embodiment in the range of30-60 μg/kg/day. In some embodiments, the amount of corticosteroid(e.g., budesonide) used in a method, in a composition or a dose of acomposition disclosed herein includes, by way of non-limiting example,about 500 μg to about 2 mg, about 1 to about 2 mg, about 1 mg, about 2mg, about 250 μg to about 20 mg, about 250 μg to about 15 mg, about 250μg to about 10 mg, about 250 μg to about 5 mg, about 250 μg to about 3mg, or about 500 μg to about 3 mg, about 375 μg to about 1.5 mg, orabout 500 μg to about 2 mg, about 1 mg to about 3 mg, about 0.25 mg,about 0.35 mg, about 0.5 mg, about 1 mg, about 2 mg, about 2.5 mg, about3 mg, about 4 mg, about 5 mg, about 6 mg, about 7 mg, about 8 mg, about9 mg, about 10 mg, or any amount suitable. In an illustrativeembodiment, the dosage is provided in a volume that reaches theesophagus in an effective amount.

In an illustrative embodiment, a dosage or amount (including a divideddose) of corticosteroid is provided in a volume that provides aneffective amount of corticosteroid to reach the targeted and/or inflamedportion of the gastrointestinal tract, including, e.g., the esophagus.In some embodiments, the effective volume of the composition coats or atleast partially coats the esophagus, and delivers the composition to theaffected areas, including by way of example only, the esophagus, aportion of the esophagus, the upper esophagus, the lower esophagus. Incertain embodiments, a composition described herein has a volume of, forexample about 5-50 mL, or for example about 5-40 mL, or for exampleabout 5-30 mL, or for example about 5-25 mL, or for example about 5-15mL, or for example about 10-25 mL, for example about 1-50 mL, or forexample about 1-40 mL, or for example about 1-30 mL, or for exampleabout 1-25 mL, or for example about 8-12 mL, or for example, about 7-8mL, or for example, about 5-25 mL, or for example about 10-20 mL, or forexample about 10 mL, or for example, about 15 mL, or for example, about20 mL, or for example about 1-15 mL, or for example about 1-10 mL, orfor example about 2-8 mL, or for example about 3-8 mL, or for exampleabout 3-7 mL, or for example, about 4-6 mL, or for example, about 5 mL,or for example about 6-14 mL, or for example, about 4-15 mL, or forexample, about 9-11 mL.

In more specific embodiments, about 0.25 mg to about 6 mg, about 0.375mg, about 0.5 mg, about 0.75 mg, about 1 mg, about 1.25 mg, about 1.5mg, or about 2 mg of corticosteroid (e.g., budesonide) is formulatedinto a single or unit dose of a pharmaceutical composition describedherein, the single or unit dose having a total volume of about 10-20 mL,or for example about 10 mL, or for example, about 15 mL, or for example,about 20 mL, or for example about 1-15 mL, or for example about 1-10 mL,or for example about 2-8 mL, or for example about 3-7 mL, or forexample, about 4-6 mL, or for example, about 5 mL, or for example about6-14 mL, or for example about 8-12 mL, or for example, about 9-11 mL, orfor example, about 10 mL.

As discussed herein, “liquid” encompasses slurries, solutions,suspensions, or any combination thereof, depending on the solubilitiesand amounts of the individual components and the vehicles and solventsused. In some embodiments, provided herein is a composition comprising acorticosteroid in a formulation used to treat a targeted portion of thegastrointestinal tract (e.g., the esophagus). In further embodiments thecomposition comprises (or is administered in) a volume used to coat atargeted portion of the gastrointestinal tract (e.g., the esophagus). Incertain embodiments the volume used to coat a targeted portion of thegastrointestinal tract (e.g., the esophagus) is a volume that issufficient to coat the targeted portion. In some embodiments, anappropriate palatable dosage is in a volume that coats or at leastpartially coats the esophagus, and in an illustrative embodiment, thevolume coats or at least partially coats the esophagus and delivers thecorticosteroid to the affected areas, including by way of example only,the esophagus, a portion of the esophagus, the upper esophagus, or thelower esophagus. In certain instances, the volume of a compositionadministered can provide a desired coating characteristic of acomposition. As such, in some embodiments, provided herein is acomposition comprising a corticosteroid wherein the compositioncomprises (or is administered in) a volume sufficient to coat a targetedportion of the gastrointestinal tract (e.g., the esophagus). In certainembodiments, likewise, is provided herein a method of treating allergicor caustic inflammation of the gastrointestinal tract, or a symptomthereof, by administering to an individual in need thereof (e.g., onediagnosed with or suspected of suffering from eosinophilic esophagitis),a composition comprising a corticosteroid and a liquid vehicle, whereinthe composition has a volume sufficient to coat (or at least coat in aeffective amount) of a targeted portion of the gastrointestinal tract(e.g. esophagus). In specific embodiments, a volume sufficient to coatthe esophagus is a volume that provides a bolus when orally administeredto an individual. In more specific embodiments, a volume sufficient tocoat the esophagus is a volume that provides a bolus along the entirelength of the esophagus (i.e., from immediately after passing the upperesophageal sphincter through the distal end of the esophagus, e.g.,immediately prior to entering or passing the lower esophageal sphincter.Thus, in certain embodiments described herein, a coating volume isoptionally utilized instead of or in addition to a coating agentdescribed herein in order to coat the targeted portion of thegastrointestinal tract (e.g., esophagus), as described herein.

In certain embodiments, provided herein are methods of treating,preventing or alleviating the symptoms of and allergic or causticinflammation associated with inflammatory disorders involving thegastrointestinal tract, including the esophagus by administering acorticosteroid to an individual in need thereof. In some embodiments,the corticosteroid is administered along the length of (e.g., the entirelength of) an afflicted or targeted surface of the gastrointestinaltract (e.g., the esophagus). In some embodiments, the corticosteroid isadministered in a composition that coats the afflicted or targetedsurface of the gastrointestinal tract (e.g., esophagus). In someembodiments, administration of corticosteroid or a composition describedherein is achieved by nebulization or aerosolization of thecorticosteroid or composition followed by swallowing (and, thereby,administration to the esophagus). In certain embodiments, administrationof a corticosteroid or a composition described herein is administeredwith a nebulizer or inhaler. In some embodiments, the inhaleradministers a composition of a corticosteroid, a vehicle (e.g., a solid,liquid or gaseous, such as a propellant, vehicle). Specific methodsuseful herein include administration from a multi-dose inhaler (MDI) ordry powder inhaler (DPI). In some embodiments, coating volumes includeany suitable amount, e.g., about 2 mL or more, about 3 mL to about 20mL, about 4 mL to about 15 mL, about 5 mL or more, about 5 mL to about20 mL, about 5 mL to about 15 mL, or about 5 mL to about 10 mL. In someembodiments, the powder delivered from the device (such as a DPI or MDI)alone is the composition which coats or is delivered along the length ofthe afflicted or targeted gastrointestinal surface (e.g., esophagus).

The dosage may, for example, be administered at least once a day, e.g.,in four, three, two, or one dose a day. In one illustrative example, thedose is provided once a day. In specific embodiments, administration ofany composition described herein (e.g., for the treatment ofgastrointestinal or esophageal inflammation including eosinophilicesophagitis) is once a day. In other specific embodiments,administration (e.g., for the treatment of gastrointestinal oresophageal inflammation including eosinophilic esophagitis) is b.i.d. Instill other embodiments, administration (e.g., for the treatment ofgastrointestinal or esophageal inflammation including eosinophilicesophagitis) is t.i.d. In yet other embodiments, administration (e.g.,for the treatment of gastrointestinal or esophageal inflammationincluding eosinophilic esophagitis) is q.i.d. In another embodiment, thedose is administered at night. In another aspect, the dose isadministered about 30 minutes prior to bed, with no food or water givenafter administration of the compositions herein. In yet anotherembodiment of the instant invention, the dose is administered prior tobedtime, wherein after administration of the composition, the patient orindividual is in a substantially supine position for at least 30minutes, at least 1 hour, at least 2 hours, at least 4 hours, at least 8hours, about 30 minutes to about 8 hours, about 30 minutes to about 4hours, about 1 hour to about 8 hours, or, about 1 hour to about 6 hours.In some embodiments provided herein, the dose is administered prior theindividual being in a substantially supine position for at least 30minutes, at least 1 hour, at least 2 hours, at least 4 hours, at least 8hours, about 30 minutes to about 8 hours, about 30 minutes to about 4hours, about 1 hour to about 8 hours, or, about 1 hour to about 6 hours.In specific embodiments, a corticosteroid or composition is administeredaccording to any method described herein, wherein administration of thecorticosteroid or composition is once a day, no more than once a day,more than once a day, twice a day, two to four times a day, three timesa day, or four times a day. In some embodiments, the administration ofthe corticosteroid or composition provided herein is administered atnight, e.g., not more than once a day at night.

In some embodiments, the corticosteroid is present in a pharmaceuticalcomposition described herein in any effective amount. In someembodiments, an effective amount is an amount sufficient to reduceinflammation or symptoms of inflammation associated with an allergic orcaustic inflammatory disorder or condition of the gastrointestinal tract(e.g., the esophagus) as compared to the level of inflammation orsymptoms of inflammation associated with an inflammatory disease priorto administration of the effective amount. In certain embodiments,effective amount is an amount sufficient to maintain a reduction ininflammation or symptoms of inflammation achieved in any mannerincluding, but not limited to, by the administration of an effectiveamount sufficient to achieve such a reduction. In some embodiments, theeffective amount is about 0.05 mg to about 10 mg, about 0.05 mg to about7.5 mg, about 0.05 mg to about 5 mg, about 0.25 mg to about 3 mg, about0.25 mg to about 2.5 mg, about 0.5 mg to about 3 mg, about 0.5 mg toabout 2 mg, about 0.5 mg to about 0.1 mg, about 0.5 mg to about 5 mg,about 0.5 mg to about 4 mg, about 1 mg to about 4 mg, about 1 mg toabout 3 mg, about 2 mg to about 3 mg, or about 2 mg to about 4 mg. Inspecific embodiments, the effective amount of corticosteroid is about0.05 mg, about 0.1 mg., about 0.15 mg., about 0.25 mg., about 0.3 mg.,about 0.35 mg, about 0.4 mg, about 0.37 mg, about 0.375 mg, about 0.7mg, about 0.8 mg, about 0.75 mg, about 1 mg, about 1.2 mg, about 1.25mg, about 1.3 mg, about 1.5 mg, about 2 mg, about 2.5 mg, about 3 mg,about 3.5 mg, about 4 mg, about 4.5 mg, about 5 mg, about 5.5 mg, about6 mg, about 6.5 mg, about 7 mg, about 6 mg or more, about 1 mg to about6 mg, about 0.25 mg to about 6 mg, about 7.5 mg or more, about 0.5 mg toabout 2 mg, about 1 to about 2 mg, about 1 mg, or about 2 mg ofcorticosteroid. In certain embodiments, the corticosteroid is present ina pharmaceutical composition at any concentration suitable for providinga therapeutically effective amount of corticosteroid to a surface of thegastrointestinal tract (e.g., the surface of the esophagus), e.g., aconcentration of about 0.01 mg/mL to about 2 mg/mL of composition. Inspecific embodiments, the corticosteroid is present in a pharmaceuticalcomposition at a concentration of about 0.01 mg/mL to about 1.5 mg/mL,about 0.03 mg/mL to about 1.5 mg/mL, about 0.05 mg/mL to about 1.5mg/mL, about 0.07 mg/mL to about 1.5 mg/mL, about 0.05 mg/mL to about0.2 mg/mL, or about 0.06 mg/mL to about 0.13 mg/mL. In more specificembodiments, the corticosteroid is present in a pharmaceuticalcomposition at a concentration of about 0.07 mg/mL to about 1 mg/mL. Insome embodiments, any composition described herein comprises an amountor concentration of corticosteroid sufficient to provide about 0.5 mg toabout 6 mg of corticosteroid per day, about 0.5 mg to about 2 mg ofcorticosteroid per day, about 1 mg to about 2 mg of corticosteroid perday, about 2 mg to about 3 mg of corticosteroid per day, about 3 mg toabout 4 mg of corticosteroid per day, about 4 mg to about 5 mg ofcorticosteroid per day, or about 5 mg to about 6 mg of corticosteroidper day. In certain embodiments, provided herein is a method of treatingallergic or caustic inflammation of the gastrointestinal tract, or asymptom thereof, by administering a sufficient amount of a compositiondescribed herein to provide about 0.5 mg to about 6 mg of corticosteroidper day, about 0.5 mg to about 2 mg of corticosteroid per day, about 1mg to about 2 mg of corticosteroid per day, about 2 mg to about 3 mg ofcorticosteroid per day, about 3 mg to about 4 mg of corticosteroid perday, about 4 mg to about 5 mg of corticosteroid per day, or about 5 mgto about 6 mg of corticosteroid per day to an individual in needthereof.

In specific embodiments, the composition described herein is acomposition comprising a corticosteroid, dextrose, maltodextrin, and aliquid vehicle. In some specific embodiments, the composition describedherein is a composition comprising a corticosteroid, maltodextrin,edetate, citrate, polysorbate (e.g., polysorbate 80), an optionalsweetener and a liquid vehicle. In specific embodiments, corticosteroidparticles (e.g., microparticles) are suspended in the aqueous medium. Incertain specific embodiments, the composition described herein is acomposition comprising a corticosteroid, dextrose and a liquid vehicle.In some specific embodiments, the composition described herein is acomposition comprising a corticosteroid and maltodextrin. In somespecific embodiments, the composition described herein is a compositioncomprising a corticosteroid and dextrose.

In other illustrative embodiments of the invention, the Budesonide isprovided in the form of a lozenge which may be dissolved in the mouth,thus reaching and coating the esophagus. The lozenge or other similartablet, capsule, or other solid, would dissolve rapidly in the mouth oresophagus to produce a solution that can then coat the esophagus. Or,for children or other patients that may have difficulty with adissolving lozenge, the lozenge may be ground or otherwise dissolved ina small volume of water or other pharmaceutically suitable liquid, forexample, reaching a total volume presented in embodiments herein. Inother illustrative embodiments of the invention, the Budesonide isprovided in the form of a tablet, a capsule, or, for example a gelcapsule, designed for slow release and delivery to the esophagus.

Initial treatment may continue, for example, for about 3 days to 2 weeksfor an acute condition, or about 4 weeks to about 16 weeks for a chroniccondition, or about 8 weeks to about 12 weeks for a chronic condition.Longer therapy may also be needed, such as, for example, therapy similarto chronic therapy for persistent asthma. Patients may, for example, betreated for up to 6 months, or up to one year. Maintenance treatment canlast up to or longer than one year. Patients may be treated on amaintenance basis or on an as needed basis during a problematic episode,depending on the severity of the condition. Patients can also be treatedon a rotating treatment basis, where treatment is provided for a periodof time and then the patient is taken off of the drug for a periodbefore treatment resumes again. When off the drug, the patient may begiven no treatment, treatment with another medication, or treatment witha reduced dosage. Or, patients may be given treatment with a higher doseof the composition until a desired reduced disease state is achieved,and then continued on a lower dose of the composition.

The methods and compositions of the present invention are used byindividuals of any age. By “individual” is meant any animal, forexample, a mammal, or, for example, a human, including, for example,patients in need of treatment. In some embodiments, the human is achild.

The compositions of the present invention may include pharmaceuticallyacceptable salts. Pharmaceutically acceptable salts are generally wellknown to those of ordinary skill in the art and may include, by way ofexample but not limitation, acetate, benzenesulfonate, besylate,benzoate, bicarbonate, bitartrate, bromide, calcium edetate, carnsylate,carbonate, citrate, edetate, edisylate, estolate, esylate, fumarate,gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate,hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide,isethionate, lactate, lactobionate, malate, maleate, mandelate,mesylate, mucate, napsylate, nitrate, pamoate (embonate), pantothenate,phosphate/diphosphate, polygalacturonate, salicylate, stearate,subacetate, succinate, sulfate, tannate, tartrate, or teoclate. Otherpharmaceutically acceptable salts may be found in, for example,Remington: The Science and Practice of Pharmacy (20^(th) ed.)Lippincott, Williams & Wilkins (2000). Preferred pharmaceuticallyacceptable salts include, for example, acetate, benzoate, bromide,carbonate, citrate, gluconate, hydrobromide, hydrochloride, maleate,mesylate, napsylate, pamoate (embonate), phosphate, salicylate,succinate, sulfate, or tartrate.

In one aspect, provided herein is an oral pharmaceutical compositioncomprising a corticosteroid and a coating agent (e.g., a viscosityincreasing agent, a mucoadhesive agent, a combination thereof, or anagent that both increases viscosity and mucoadhesion). In variousaspects, an exemplary corticosteroid is budesonide,16,17-(butylidenebis(oxy))-11,21-dihydroxy-,(11-β,16-α)-pregna-1,4-diene-3,20-dione.

Depending on the specific conditions being treated, the compositions maybe formulated into liquid or solid dosage forms and administeredsystemically or locally. The agents may be delivered, for example, in atimed- or sustained-low release form as is known to those skilled in theart. Techniques for formulation and administration may be found inRemington: The Science and Practice of Pharmacy (20th ed.) Lippincott,Williams & Wilkins (2000).

In certain embodiments, the pharmaceutical compositions provided hereinare used to treat, prevent or alleviate allergic or caustic inflammatorydiseases involving the gastrointestinal tract, including the esophagus.In some embodiments, the pharmaceutical composition is in liquid form.Liquid forms include, by way of non-limiting example, emulsions,solutions, suspensions, syrups, slurries, dispersions, colloids and thelike. Also provided are pharmaceutical compositions comprising acorticosteroid (e.g., a topical corticosteroid, such as, for example,budesonide) and a coating agent (e.g., a mucoadhesive agent) in the formof a dissolving tablet, a dissolving wafer, a capsule, or a gel capsule.In some embodiments, a pharmaceutical composition described herein is inliquid, semi-solid or solid (e.g., powder) form. In specificembodiments, a pharmaceutical composition described herein is insemi-solid form, e.g., a gel, a gel matrix, a cream, a paste, or thelike. In some embodiments, semi-solid forms comprise a liquid vehicle.In some embodiments, semi-solid forms comprise a liquid vehicle. In someembodiments, the solid form is a solid dosage form, such a tablet, or apowder. In certain embodiments, solid dosage forms described hereincomprise a solid vehicle (e.g., as used in a tablet), and/or a gaseousvehicle (e.g., as used in DPI).

In addition to the active or actives, various embodiments of the presentinvention provide for pharmaceutical compositions that contain suitablepharmaceutically carriers comprising, e.g., acceptable excipients and/orauxiliaries. For example, in some embodiments, pharmaceuticallyacceptable carriers (e.g., excipients and/or auxiliaries) are used toformulate the corticosteroids herein disclosed for the practice of theinvention into dosages suitable for systemic administration is withinthe scope of the invention. In some embodiments, the corticosteroid isformulated readily using pharmaceutically acceptable carriers (e.g.,excipients and/or auxiliaries) well known in the art into dosagessuitable for oral administration. Such carriers (e.g., excipients and/orauxiliaries) enable the compositions of the invention to be formulatedas tablets, pills, dragees, capsules, liquids, soft chews, creams,pastes, chewable tablets, gels or gel matrices, gums, syrups, slurries,suspensions, lozenges, and the like, for oral ingestion by a patient tobe treated. In certain instances, oral formulations (e.g., suspensions,creams or gel matrices) are formulated such that upon oraladministration, an interface layer between the oral formulation (e.g.,suspension, cream or gel matrix) and a gastrointestinal surface (e.g.,mucosal membrane or epithelium) is formed. In some instances, an oralformulation (e.g., suspensions, creams or gel matrices) in contact witha mucosal membrane delivers a corticosteroid to the mucosal membrane viathe interface layer and as the oral formulations (e.g., suspensions,creams or gel matrices) near the interface layer is depleted ofcorticosteroid, a concentration gradient results. In certain instancesan osmotic delivery of corticosteroid may occur. In some instances,portions of the oral formulations (e.g., suspensions, creams or gelmatrices) with high concentrations of corticosteroid, relative to theportions of the oral formulations (e.g., suspensions, creams or gelmatrices) proximate to the interface layer, replenishes corticosteroidin the portion of the oral formulations (e.g., suspensions, creams orgel matrices) proximate to the interface layer. In certain instances,upon oral administration of an oral formulation described herein to anindividual, an interface layer is formed between a gastrointestinalsurface (e.g., an esophageal mucosa/epithelium) and a mixture of theoral formulation (e.g., lozenge or dissolving or chewable tablet) andsaliva of the individual.

Pharmaceutical preparations for oral use may be obtained by combiningthe corticosteroids with solid excipients, optionally grinding aresulting mixture, and processing the mixture of granules, after addingsuitable auxiliaries, if desired, to obtain tablets or dragee cores.Suitable excipients are, in particular, fillers such as sugars,including lactose, sucrose, sucralose (Splenda®, Distributed By: McNeilNutritionals, LLC, Fort Washington, Pa. 19034-2299), mannitol, orsorbitol; cellulose preparations, for example, maize starch, wheatstarch, rice starch, potato starch, gelatin, gum tragacanth, methylcellulose, hydroxypropylmethyl-cellulose, sodium carboxymethyl-cellulose(CMC), and/or polyvinylpyrrolidone (PVP: povidone). If desired,disintegrating agents may be added, such as the cross-linkedpolyvinylpyrrolidone, agar, or alginic acid or a salt thereof such assodium alginate. For dissolving tablets, appropriate excipients includethose that increase the resulting liquid viscosity of the dissolvedtablet, enabling it to reach the esophagus, for example, to coat theesophagus. Appropriate excipients may also, for example, include thosethat render the dissolving tablet palatable, such as sweeteners.

For liquid form, appropriate excipients may be added to increase thecoating ability, liquid viscosity and/or the mucoadhesive character ofthe liquid composition. Appropriate excipients may also, for example,include those that render the liquid composition palatable. Excipientsmay include, for example, either sugars, including lactose, sucrose,sucralose (Splenda®, Distributed By: McNeil Nutritionals, LLC, FortWashington, Pa. 19034-2299), maltodextrin, dextrose, mannitol, orsorbitol; honey; cellulose preparations, for example, maize starch,wheat starch, rice starch, potato starch, gelatin, gum tragacanth,methyl cellulose, hydroxypropylmethyl-cellulose, acarboxymethyl-cellulose (CMC) (e.g., sodium carboxymethyl-cellulose(NaCMC)), and/or polyvinylpyrrolidone (PVP: povidone).

Viscosity-enhancing excipients that are optionally utilized in certainembodiments of the pharmaceutical compositions described herein include,by way of non-limiting example, a crosslinked poly(acrylic acid) (e.g.,Carbopol 974P), glycerine, a carbomer homopolymer, a carbomer copolymer,acacia (gum arabic), agar, aluminum magnesium silicate, sodium alginate,sodium stearate, bladderwrack, bentonite, carbomer, carrageenan,Carbopol, cellulose, ceratonia, chondrus, dextrose, furcellaran,gelatin, Ghatti gum, guar gum, hectorite, lactose, sucrose,maltodextrin, mannitol, sorbitol, honey, maize starch, wheat starch,rice starch, potato starch, gelatin, sterculia gum, xanthum gum,polyethylene glycol (e.g. PEG 200-4500) gum tragacanth, ethyl cellulose,ethylhydroxyethyl cellulose, ethylmethyl cellulose, methyl cellulose,hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropylcellulose, poly(hydroxyethyl methacrylate), oxypolygelatin, pectin,polygeline, povidone, propylene carbonate, methyl vinyl ether/maleicanhydride copolymer (PVM/MA), poly(methoxyethyl methacrylate),poly(methoxyethoxyethyl methacrylate), hydroxypropyl cellulose,hydroxypropylmethyl-cellulose, carboxymethyl-cellulose (CMC) (including,e.g., sodium carboxymethyl-cellulose (NaCMC)), silicon dioxide,polyvinylpyrrolidone (PVP: povidone), Splenda® or combinations thereof.

Mucoadhesive agents to be used herein include, by way of non-limitingexample, a soluble polyvinylpyrrolidone polymer (PVP), a carbopol, acrosslinked poly(acrylic acid) (e.g., Carbopol 974P), a carbomerhomopolymer, a carbomer copolymer, a water-swellable, butwater-insoluble, fibrous, cross-linked carboxy-functional polymer, ahydrophilic polysaccharide gum, one or more maltodextrin, alginate, across-linked aliginate gum gel, thiomers (e.g., thiolated chitosan,thiolated polycarbophil, thiolated alginate, thiolated cellulosederivatives, thiolated carboxymethyl cellulose, thiolated polyacrylicacid, or thiolated polyacrylates), PEGylated polymers (e.g., PEGylatedpolyacrylic acid or PEGylated polyacrylates), lectin, hydroxypropylmethyl cellulose (HPMC), cellulose derivatives, HPMA copolymers, awater-dispersible polycarboxylated vinyl polymer. In some embodiments,the mucoadhesive agent is a carbopol. In a specific embodiment, themucadhesive agent is selected from, by way of non-limiting example,Carbopol 974P, Carbopol Ultrez 10, sodium alginate LF120 and sodiumalginate H120L.

In some embodiments, mucoadhesive agents that may be used in certainembodiments of the compositions and methods described herein aredescribed, for example, in U.S. Pat. Nos. 6,638,521, 6,562,363,6,509,028, 6,348,502, 6,306,789, 5,814,330, and 4,900,552, each of whichis hereby incorporated by reference in its entirety.

In one non-limiting example, a mucoadhesive agent can be, by way ofnon-limiting example, at least one or at least two particulatecomponents selected from titanium dioxide, silicon dioxide, and clay. Insome embodiments, when the composition is not further diluted with anyliquid prior to administration, the level of silicon dioxide is fromabout 3% to about 15%, by weight of the composition. In certainembodiments, silicon dioxide is selected from, by way of non-limitingexample, fumed silicon dioxide, precipitated silicon dioxide,coacervated silicon dioxide, gel silicon dioxide, and mixtures thereof.In some embodiments, clay is selected from, by way of non-limitingexample, kaolin minerals, serpentine minerals, smectites, illite ormixtures thereof. In certain embodiments, clay is selected from, by wayof non-limiting example, laponite, bentonite, hectorite, saponite,montmorillonites or mixtures thereof.

In some embodiments, compositions described herein comprisemaltodextrin. In some embodiments, compositions described hereincomprise about 0.05 g of maltodextrin per mL of liquid vehicle to about0.6 g of maltodextrin per mL of liquid vehicle. In certain embodiments,compositions described herein comprise about 0.1 g of maltodextrin permL of liquid vehicle to about 0.6 g of maltodextrin per mL of liquidvehicle. In certain embodiments, compositions described herein compriseabout 0.2 g of maltodextrin per mL of liquid vehicle to about 0.5 g ofmaltodextrin per mL of liquid vehicle. In some embodiments, compositionsdescribed herein comprise about 0.1 g of maltodextrin per mL of liquidvehicle to about 0.4 g of maltodextrin per mL of liquid vehicle. Incertain embodiments, compositions described herein comprise about 0.2 gof maltodextrin per mL of liquid vehicle to about 0.4 g of maltodextrinper mL of liquid vehicle. In some embodiments, compositions describedherein comprise about 0.2 g of maltodextrin per mL of liquid vehicle toabout 0.3 g of maltodextrin per mL of liquid vehicle. In certainembodiments, compositions described herein comprise about 0.25 g ofmaltodextrin per mL of liquid vehicle to about 0.28 g of maltodextrinper mL of liquid vehicle. In some embodiments, compositions describedherein comprise about 0.1 g of maltodextrin per mL of liquid vehicle,about 0.15 g of maltodextrin per mL of liquid vehicle, about 0.2 g ofmaltodextrin per mL of liquid vehicle, about 0.25 g of maltodextrin permL of liquid vehicle, about 0.3 g of maltodextrin per mL of liquidvehicle, about 0.35 g of maltodextrin per mL of liquid vehicle, about0.4 g of maltodextrin per mL of liquid vehicle, about 0.45 g ofmaltodextrin per mL of liquid vehicle, about 0.5 g of maltodextrin permL of liquid vehicle, about 0.55 g of maltodextrin per mL of liquidvehicle, or about 0.6 g of maltodextrin per mL of liquid vehicle.

In some embodiments, a coating agent utilized herein comprisesmaltodextrin.

In some embodiments, a mucoadhesive agent utilized in an oralpharmaceutical composition described herein imparts an increasedviscosity upon the oral pharmaceutical composition (e.g., compared to anotherwise identical composition lacking the mucoadhesive agent).

Any of the compositions or formulations described herein optionallycomprise one or more viscosity enhancing agent, optionally comprise oneor more binder, optionally comprise one or more filler, optionallycomprise one or more lubricant, optionally comprise one or more solvent,optionally comprise one or more sweetener, optionally comprise one ormore antioxidant, optionally comprise one or more buffering agent,optionally comprise one or more surfactant, or combinations thereof.

Buffering agents include, by way of non-limiting example, citratebuffers (i.e., citric acid and citrate), phosphate buffers, acetatebuffers, combinations thereof, or the like.

As used herein, “citrate” includes all compounds of Formula I whereineach R is independently selected from an H and a negative charge (e.g.,as a salt or as a disassociated salt or acid). In certain embodiments,citrate is selected from, by way of non-limiting example, sodiumcitrate, citric acid and the like.

Antioxidants include, by way of non-limiting example, ascorbylpalmitate, butylated hydroxyanisole, butylated hydroxytoluene,monothioglycerol, sodium ascorbate, sodium formaldehyde sulfoxylate,sodium metabisulfite, BHT, BHA, sodium bisulfite, vitamin E or aderivative thereof, propyl gallate, combinations thereof, or the like.Compositions and formulations described herein optionally include ofabout 0.01% w/w to about 0.5% w/w, about 0.01% w/w to about 0.3% w/w, orabout 0.01% w/w to about 0.1% w/w one or more antioxidant(s).

In some embodiments, antioxidants include, by way of non-limitingexample, edetate (EDTA) (e.g., disodium edetate),Diethylenetriaminepentaacetic acid (DTPA), Triglycollamate (NT), or thelike. Compositions and formulations described herein optionally includeabout 0.01% w/w to about 0.5% w/w, about 0.01% w/w to about 0.3% w/w, orabout 0.01% w/w to about 0.1% w/w, or about 0.05% w/w of edetate (orsalt thereof).

As used herein, “edetate” includes all compounds of Formula II whereineach R is independently selected from an H and a negative charge (e.g.,as a salt or as a disassociated salt or acid). In certain embodiments,edetate is selected from, by way of non-limiting example, disodiumedetate, calcium edetate, ethylenediaminetetraacetic acid and the like.

In certain embodiments, sweeteners include, by way of non-limitingexample, glycerin, sucrose, lactose, glucose, fructose, arabinose,xylose, ribose, mannose, galactose, dextrose, sorbose, sorbitol,mannitol, maltose, cellobiose, xylitol and the like.

Surfactants include, e.g., anionic, cationic, non-ionic, or zwitterionicsurfactants, such as, by way of non-limiting example, polysorbate (e.g.,polysorbate 20, polysorbate 60, polysorbate 40, polysorbate 80,polysorbate 81, polysorbate 85, polysorbate 120), bile acids or theirsalts (e.g., sodium taurocholates, sodium deoxytaurocholates,chenodeoxycholic acid, and ursodeoxycholic acid), nonoxynol orpolyoxyethylene glycol fatty acid esters, pluronic or poloxamers such asPluronic F68, Pluronic L44, Pluronic L101, combinations thereof, or thelike. Compositions and formulations described herein optionally includeabout 0.001% w/w to about 0.5% w/w, about 0.001% w/w to about 0.3% w/w,or about 0.001% w/w to about 0.1% w/w of one or more surfactant.

Dragee cores are provided with suitable coatings. For this purpose,concentrated sugar solutions may be used, which may optionally containgum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethyleneglycol (PEG), and/or titanium dioxide, lacquer solutions, and suitableorganic solvents or solvent mixtures. Dye-stuffs or pigments may beadded to the tablets or dragee coatings for identification or tocharacterize different combinations of active corticosteroid doses.

Pharmaceutical preparations that may be used orally also includepush-fit capsules made of gelatin, as well as soft, sealed capsules madeof gelatin, and a plasticizer, such as glycerol or sorbitol. Thepush-fit capsules can contain the active ingredients in admixture withfiller such as lactose, binders such as starches, and/or lubricants suchas talc or magnesium stearate and, optionally, stabilizers. In softcapsules, the corticosteroids may be dissolved or suspended in suitableliquids, such as fatty oils, liquid paraffin, or liquid polyethyleneglycols (PEGs). In addition, stabilizers may be added.

In some embodiments, the corticosteroid is administered in acommercially available formulation. In other embodiments, thecorticosteroid is administered in a composition comprising acommercially available formulation of a corticosteroid. For example, insome embodiments, the corticosteroid containing composition comprises acommercially available formulation and an excipient, such as a coatingagent or an excipient that imparts a mucoadhesive characteristic to thecomposition, and/or a diluent. In some embodiments, wherein thecorticosteroid is budesonide, the commercially available formulation isPulmicort Respules®. In certain embodiments, a composition providedherein comprises (1) commercially available micronized corticosteroidparticles (e.g., micronized budesonide), or other commercially availablecorticosteroid particles; and (2) a diluent or vehicle (e.g., an aqueousliquid vehicle) to provide a composition as described herein (e.g., onehaving a volume sufficient to coat the esophagus). In some embodiments,a composition provided herein comprises (1) commercially availablemicronized corticosteroid particles (e.g., micronized budesonide), orother commercially available corticosteroid particles; (2) an excipientthat increases the interaction of the composition and/or corticosteroidwith a surface of the gastrointestinal tract (e.g., esophagus); and (3)optionally a diluent or vehicle (e.g., an aqueous liquid vehicle) toprovide a composition as described herein (e.g., one having a volumesufficient to coat the esophagus). In specific embodiments, thecommercially available micronized corticosteroid particles are providedin a suspension, e.g., a commercially available suspension such asPulmicort Respules®. In certain embodiments, provided herein is a methodof preparing such a composition by combining each of the components andmixing them together.

In certain embodiments, the corticosteroid containing compositioncomprises micronized budesonide, disodium edetate, sodium chloride,sodium citrate, citric acid, polysorbate (e.g., polysorbate 80), water,and optionally one or more excipients, wherein the excipients areselected from any of those recited herein. In certain embodiments, thecomposition comprises about 0.1 mg to about 1.0 mg budesonide/2 mL (orabout 0.05 mg to about 0.5 mg per gram) of composition. In someembodiments, the composition comprises about 0.2 mg to about 0.6 mgbudesonide/2 mL (or about 0.1 mg to about 0.3 mg per gram) ofcomposition. In specific embodiments, the composition comprises about0.25 mg/2 mL composition. In other specific embodiments, the compositioncomprises about 0.5 mg/2 mL composition.

In one illustrative embodiment, the corticosteroid of the compositionhas a low bioavailability, so that much of it will remain in thegastrointestinal tract, for example, in the esophagus. This may resultin decreased systemic side effects and complications, allowing patientswith chronic conditions to receive treatment for longer periods of time.In certain embodiments, provided herein is a method of orallyadministering a composition comprising a corticosteroid wherein systemicexposure of corticosteroid is reduced (e.g., significantly reduced)compared to the pulmonary administration of a nebulized or aerosolizedcorticosteroid composition with the same nominal or delivered dose. Insome embodiments, provided herein is a method of orally administering(e.g., by drinking) a composition comprising a corticosteroid whereinsystemic exposure of corticosteroid is reduced (e.g., significantlyreduced) compared to the oral administration of a nebulized oraerosolized corticosteroid composition (which is sprayed on the targetedsite of the gastrointestinal site, e.g., esophagus) comprising acorticosteroid. In some embodiments, the area under the curve(AUC_(0-∞)) for the plasma concentration of an orally administeredcorticosteroid composition described herein to the gastrointestinaltract according to any methods described herein is less than 90%, lessthan 80%, less than 70%, less than 60%, between 50% and 90%, between 0%and 40%, less than 50%, less than 40%, less than 30%, less than 20%, orless than 10% of the area under the curve (AUC_(0-∞)) for the plasmaconcentration of an inhaled corticosteroid (e.g., Pulmicort) having thesame delivered dose (or dose adjusted for the same dose as administeredorally).

Viscosity

Excipients, such as, for example, those listed herein, may be includedin the composition to increase the viscosity of the deliveredcomposition. The liquid viscosity may be increased in the oral form, orthe excipient may increase the viscosity of the dissolved form of atablet. Those of ordinary skill in the art will recognize that theviscosity should be at a level that is sufficient to deliver aneffective amount of the composition to the esophagus, for example, in anamount that may coat the esophagus. Also, the viscosity should be at alevel that may be given orally, thus not so thick that it is either toodifficult to swallow, causes gagging, or is unpalatable. Those ofordinary skill in the art may determine the viscosity of thecompositions provided in the Examples, and may thus determineappropriate ranges. One method of determining whether the composition issufficiently viscous is by determining whether the inflammation, oreosinophilic infiltration, of the esophagus is reduced after treatmentwith the corticosteroid.

Viscosity can be determined by any method that will measure theresistance to shear offered by the substance or preparation. Manyviscometers are available to those in the pharmaceutical field, andinclude those built by, for example, Brookfield. Viscosity may be, forexample, measured at room temperature, at about 20-25 degrees Celsius,or at about 37 degrees Celsius to mimic body temperature. The viscosityof a liquid generally decreases as the temperature is raised. In someembodiments of the invention, the viscosity is about the viscosity ofabout 1 grams, about 2 grams, about 3 grams, about 4 grams, about 5grams, about 6 grams, about 7 grams, about 8 grams, about 9 grams, about10 grams, about 11 grams, about 12 grams, about 13 grams, about 14grams, about 15 grams, about 1 to about 5 grams, about 1 to about 50grams, or about 5 to about 25 grams of sucralose (Splenda®, DistributedBy: McNeil Nutritionals, LLC, Fort Washington, Pa. 19034-2299), or about7 to about 20 grams of sucralose (Splenda®), or about 5 to about 15grams of sucralose (Splenda®), or about or about 7 to about 15 grams ofsucralose (Splenda®), or about 8 to about 12 grams of sucralose(Splenda®), or about 10 to about 11 grams of sucralose (Splenda®), addedto 4 ml water, at 25 degrees Celsius. In an illustrative embodiment, theviscosity is about the viscosity of 10 grams of sucralose (Splenda®)added to 4 ml of water, at 25 degrees Celsius. In other embodiments, theviscosity is about the viscosity of 5 to 20 grams of sucralose(Splenda®) in 8 ml total liquid volume, at 25 degrees Celsius. In otherembodiments, the viscosity is about the viscosity of 5 to 15 grams ofsucralose (Splenda®) in an 8 ml total liquid volume, at roomtemperature. In other embodiments, the viscosity is about the viscosityof 8 to 12 grams of sucralose (Splenda®) in an 8 ml total liquid volumeat 25 degrees Celsius. In some embodiments, the viscosity is betweenthat of about a fruit nectar and commercial honey, where the viscosityis measured at 25 degrees Celsius.

In some embodiments, the viscosity of a composition provided herein isat least 2 centipoise (cP), at least 5 cP, at least 10 cP, at leastabout 25 cP, at least about 30 cP, at least about 35 cP, at least about40 cP, at least about 50 cP, at least about 200 cP, at least about 225cP, about 2 cP to about 10 cP, about 2 cP to about 25 cP, about 2 cP toabout 50 cP, about 20 cP to about 50 cP, about 20 cP to about 100 cP, orabout 50 cP to about 100 cP. In some embodiments, the viscosity of thecomposition is at least about 100 cP. In certain embodiments, theviscosity of the composition, measured at about 25 degrees Celsius, isabout 50 cP to about 250,000 cP, about 50 cP to about 70,000 cP, about50 cP to about 25,000 cP, about 50 cP to about 10,000 cP, about 50 cP toabout 3,000 cP, or about 50 cP to about 2,000 cP. In one aspect, theviscosity of the composition, as measured at about 25 degrees Celsius,is from about 25 centipoise (cP) to about 800 cP, about 50 cP to about800, or about 300 cP to about 800 cP (e.g., measured by a Brookfieldviscometer). In another aspect, the viscosity of the composition mayrange from about 100 cP to about 200 cP, about 200 cP to about 300 cP,about 250 cP to about 600 cP or about 400 cP to about 600 cP. Inspecific embodiments, the viscosity of the formulation is about 30 cP,about 100 cP, about 200 cP, about 300 cP, about 400 cP, about 500 cP, orabout 250,000 cP (e.g., as measured with a Brookfield viscometer atabout 25 degrees Celsius equipped with an ultra low adapter).

In some embodiments, the viscosity of a composition provided herein ismeasured at room temperature (about 25 degrees C.) with a shear rate ofabout 13.2 sec⁻¹ (e.g., with gap between the spindle and sample chamberwall of about 6.0 mm). In certain embodiments, provided herein is acomposition having a viscosity under such conditions that is at least 2centipoise (cP), at least 5 cP, at least 10 cP, at least about 25 cP, atleast about 30 cP, at least about 35 cP, at least about 40 cP, at leastabout 50 cP, at least about 200 cP, at least about 225 cP, at leastabout 250 cP, at least about 300 cP, or at least about 400 cP. In someembodiments, the viscosity of the composition under such conditions isabout 50 cP to about 250,000 cP, about 50 cP to about 70,000 cP, about50 cP to about 25,000 cP, about 50 cP to about 10,000 cP, about 50 cP toabout 3,000 cP, about 50 cP to about 2,000 cP, about 250 cP to about250,000 cP, about 250 cP to about 70,000 cP, about 250 cP to about25,000 cP, about 250 cP to about 10,000 cP, about 250 cP to about 3,000cP, or about 250 cP to about 2,000 cP. In one aspect, the viscosity ofthe composition, as measured at about 25 degrees Celsius, is from about25 centipoise (cP) to about 800 cP, about 50 cP to about 800, or about300 cP to about 800 cP (e.g., measured by a Brookfield viscometer). Inanother aspect, the viscosity of the composition under such conditionsmay range from about 100 cP to about 200 cP, about 200 cP to about 300cP, about 250 cP to about 600 cP or about 400 cP to about 600 cP. Inspecific embodiments, the viscosity of the formulation measured undersuch conditions is about 30 cP, about 40 cP, about 100 cP, about 200 cP,about 300 cP, about 400 cP, about 500 cP, or about 250,000 cP.

In certain embodiments, a pharmaceutical composition described herein isa non-newtonian fluid. In some specific embodiments, the non-newtonianfluid is thixotropic. In certain embodiments, the non-newtonian fluidcomposition thins with shear, and thickens upon the absence of shear.

Example 1

Patient 1 was a 6-year-old male with a history of abdominal pain,failure to thrive, and vomiting since infancy, and developmental delaywith isolated EE diagnosed in 2001. His allergic history was significantfor allergic rhinitis secondary to cat, dog, and dust mite exposure aswell as positive Pharmacia CAP radioallergosorbent testing for fish andmilk. Following upper gastrointestinal endoscopy (EGD) with esophagealbiopsies demonstrating a maximum eosinophil count of 60 per high-poweredfield (hpf at 400× magnification) he was diagnosed with EE and treatedwith oral corticosteroid (prednisone 0.5 mg per kg daily) for one month.This resulted in resolution of esophageal eosinophilia with a maximum of2 eosinophils per hpf on repeat EGD with biopsy. He was subsequentlytreated with omeprazole (Prilosec®) 10 mg twice daily and fluticasone(Flovent®) 220 ug twice daily as topical esophageal therapy but repeatEGD with biopsy after 6 months demonstrated a maximum eosinophil countof 50 per hpf. His therapeutic regimen was changed to elemental formulaand fluticasone but repeat EGD with biopsy demonstrated persistentesophageal eosinophils with a maximal eosinophil count of 74 per hpfaccompanied by basal zone hyperplasia. He was referred to Children'sHospital Eosinophilic Gastrointestinal Disorders clinic for furthermanagement of EE recalcitrant to usual therapy. At the time of hisreferral, he continued to have vomiting and poor weight gain and hismother reported significant difficulty with the puff and swallowtechnique. He was placed on a regimen of twice daily oral budesonidesuspension (Pulmicort®) 500 micrograms (4 ml) mixed with about 10packets (1 gram each) sucralose, (Splenda®), a non-absorbed sugar inorder to increase fluid viscosity to be swallowed twice daily. The totalvolume of the preparation was about 7 to 8 ml. Following 3 months oftherapy, repeat EGD showed a normal esophagus and biopsies demonstratedcomplete resolution of both esophageal eosinophils and basal zonehyperplasia. In addition, his abdominal pain and vomiting resolved,resulting in increased appetite with documented weight gain. Eight amcortisol was 13.2 mcg/dL (normal range for age 3-15 mcg/dL) after fourmonths of therapy.

Example 2

Patient 2 was a 5-year-old girl with a history of developmental delay,abdominal pain, and RAST positivity for milk, egg, and wheat. EGD showeda normal esophagus but histopathology of biopsies demonstrated maximaleosinophil counts of 40 per hpf and basal zone hyperplasia. She wasplaced on a hydrolyzed formula containing milk protein (Peptamen Jr®),omeprazole 10 mg twice daily and oral cromolyn (Gastrocrom®) 100 mg fourtimes daily. Following 12 months of therapy, repeat EGD demonstrated apale, furrowed esophagus with maximum eosinophil counts of 94, 65, and90 per hpf and diffuse basal zone hyperplasia in the distal, mid, andproximal esophagus, respectively. She was referred to the Children'sHospital Eosinophilic Gastrointestinal Disorders clinic for furthermanagement. Subsequent skin prick testing showed a positive response toher hydrolyzed milk protein containing formula and her diet was changedto elemental formula. After two months of elemental formula and oralcromolyn sodium, EGD was unchanged with a pale, furrowed esophagus andmaximal eosinophil counts of 100, 90, and 70 per hpf in the distal, mid,and proximal esophagus with diffuse basal zone hyperplasia. Herdevelopmental delay precluded the use of a fluticasone inhaler devisewith puff and swallow technique. As an alternative, she received oralbudesonide 500 micrograms (Pulmicort®) mixed with sucralose (Splenda®)twice daily as topical esophageal therapy. Following 3 months ofbudesonide, she had improvement in her abdominal pain and EGD revealed anormal appearing esophagus with improved maximum eosinophil counts of28, 20, and 5 per hpf in the distal, mid, and proximal esophagus anddecreased basal zone hyperplasia.

Example 3 Multi-Patient Retrospective Review

This example details the efficacy and safety of once daily oral viscousbudesonide (OVB) in inducing and maintaining remission of diseaseactivity in children with EE. The results of this study show that in 20children (mean age 5.5 yrs) the mean highest eosinophil count was 87eos/hpf (range 30-170) before and 7 eos/hpf (range 0-50, p<0.0001) aftertherapy. There were 16 (80%) responders, 1 partial-responder and 3non-responders. The mean symptom score fell from 4.4 to 0.8 (p<0.0001)and the mean endoscopy score from 3.6 to 0.8 (p<0.0001). No significantadverse events were reported. Morning cortisol levels were within normallimits. Methods.

This retrospective review was approved by Children's Hospital, San Diego(CHSD) and University of California at San Diego (UCSD), Human ResearchProtection Program. Patients were referred from CHSD subspecialtyclinics and other institutions to the EE clinic. Some patients receivedprevious therapy with proton pump inhibitor, elimination diet based uponskin or blood allergy testing, elimination diet or topical fluticasoneproprionate only after the diagnosis of EE was established. Patients whoreceived these therapies, refused elimination diet, or were unable toutilize fluticsone prorionate MDI but continued to have 24 eos/hpf onesophageal biopsy were offered OVB. Patients were defined as having foodor aeroallergen sensitization if RAST and/or skin prick testing werepositive. No changes were made to longstanding therapy used for treatingchronic conditions such as asthma or eczema and none of the childrenreceived concurrent immune-modulatory treatment. Morning cortisolmeasurements were available only in 13 patients as this test was notinitially performed routinely.

Upper Gastrointestinal Endoscopy and Biopsy. Endoscopy was performedusing the Olympus P160 endoscope (by RD) and pan-esophageal, gastric andduodenal biopsies were taken. Eosinophilic esophagitis was diagnosedwhen 24 eos/hpf were found in at least one of the esophageal sitesbiopsied. Two mucosal biopsies were taken from the proximal esophagus (3cm below the crycopharyngeus muscle), distal esophagus (3 cm above thegastroesophageal junction (GEJ), and mid-esophagus (midpoint between thecrycopharyngeus muscle and the GEJ). Biopsies were processed routinelyand evaluated by a pediatric pathologist (RN). The highest number ofeosinophils per ×400 high power field were counted [FIG. 1]. Basal zonehyperplasia (BZH) is reported when basal zone cells extend towards theluminal surface of the epithelium (>25% of epithelial thickness).

Follow-up endoscopy with biopsies were taken after 3-4 months treatmentOVB. Counting the highest number of eos/hpf within biopsies determinedthe response to therapy and patients were categorized into responders(0-7 eos/hpf), partial-responders (8-23 eos/hpf) and non-responders (≧24eos/hpf).

An EE Endoscopy Score was devised to compare findings before and aftertreatment. It was calculated from procedure reports and photographs.Four categories, (1) pallor and diminished vascular markings; (2)furrowing with “thickened” mucosa; (3) white mucosal plaques; (4)concentric rings or strictures. For each category, one point wasallocated if 1 or 2 esophageal sites were involved, and two points forpan-esophageal involvement. The maximum score was 8.

Treatment. Patients received OVB 0.5 to 2 mg daily and were instructednot to ingest any solids or liquids for 30 minutes afterwards. Viscousbudesonide was made by mixing each 0.5 mg Pulmicort™ respule with 5grams (5 packets) of sucralose (Splenda™) to create a volume of 8-12 ml.A Pulmicort Respule™ is liquid budesonide intended for nebulizedadministration (0.5 mg budesonide/2 ml). No dietary changes were made inpatients already on dietary restrictions. All patients receivedconcurrent acid-suppression therapy.

Symptoms. A modified symptom score based on children with acid-pepticdisease is used routinely in the EE clinic (31). The symptom categoriesinclude (1) heartburn or regurgitation; (2) abdominal pain orunexplained irritability in younger children; (3) nausea or vomiting;(4) anorexia or early satiety; (5) dysphagia or odynophagia, (6)nocturnal wakening with symptoms; (7) gastrointestinal bleeding(previous 4 months). Each category scored 0-2 points with a maximum of14 points. Zero points were awarded if the symptom was absent; one pointif the symptom was mild, did not interfere with daily activities; 2points if the symptoms were severe enough to interrupt daily activities.Previous GI bleeding was considered mild (1 point) if there was noassociated hemodynamic compromise or anemia, and severe (2 points) ifbleeds were multiple, caused anemia, or required blood transfusion.

Statistical Analysis.

All statistical analysis was carried out using NCSS Statistical SoftwardPackage. Two-tailed p values were calculated using paired t-tests tocompare the means of patient values for eos/hpf, EE Endoscopy Scores andSymptom Scores before and after budesonide therapy. Two-tailed unpairedt-tests were utilized in order to compare variables grouped byresponders versus non-responders. Spearman's correlation coefficientswere generated using GraphPad Prism software. Results with p values<0.05 were considered statistically significant. Both mean and medianstatistics were generated, both were equivalent and mean statistics arepresented.

Results.

Subjects. Chart reviews were undertaken on twenty children with a meanage of 5.5 years (range 1.7 to 17.6 yrs). Fifteen were Caucasian, 2Hispanic, 2 Asian, and 1 African American. Three children haddevelopmental delay (1 cerebral palsy, 1 autism, 1 Rett's Syndrome) andone had mild IgG deficiency (321 mg/dl, reference range 423-1090 mg/dl).None had H. pylori infection. Fourteen children had asthma, eczemaand/or allergic rhinitis, 16 had sensitization to foods based onpositive skin and/or RAST testing (Table 1). Prior to OVB, 6 childrenreceived a restriction diet (3 with concurrent elemental formula), 5received topical fluticasone proprionate and 5 children received protonpump inhibitor (PPI) therapy. An additional 5 children received PPItherapy with either fluticasone proprionate or diet. All of thesepreviously treated children had >24 eos/hpf on repeat esophageal biopsybefore starting OVB therapy. [Table 1].

Mean morning cortisol levels measured in 18 patients was 9.5 ug/dL(patient range 6-17 ug/dL, normal range 2-17 ug/dL,). Seventeen childrengained weight during treatment at a mean rate of 0.42 kg/month. Noadverse effects attributable to OVB were noted except for one child withlow IgG who developed esophageal candida.

Treatment. Patients received OVB for a mean of 3.6 months before repeatendoscopy. Fifteen patients received OVB 1 mg/day, four received 2mg/day and one unintentionally received 0.5 mg/day [Table 1]. In someembodiments of the invention, 0-1 mg/day, 1-2 mg/day, 2-3 mg/day, 34mg/day, 4-5 mg/day, or 5-6 mg/day of corticosteroid, for example topicalcorticosteroid, for example, Budesonide, are administered to a patient.

Histology. Before treatment the mean highest eosinophil count for allpatients, for all sites was 87 eos/hpf (95% CI 72-103), with a mean of80 eos/hpf (95% CI 66-94) in the distal, 53 eos/hpf (95% CI 37-68) inthe mid and 43 eos/hpf (95% CI 24-61) in the proximal esophagus. Thehighest eosinophil count was found in distal esophageal biopsies in 14,mid-esophageal in 3 and proximal esophageal biopsies in 3 patients. Tenpatients (50%) had pan-esophageal BZH. The mean highest gastric andduodenal eosinophil count was 1 eos/hpf (range 0-5). Followingtreatment, the mean highest eosinophil count for all patients was 7eos/hpf (95% CI 1-13, p<0.0001). All patients had a decreased eosinophilcount with mean levels of 9 (95% CI 9-14) in distal, 5 (95% CI 1-9) inmid and 2 eos/hpf (95% CI 1-5) in the proximal esophagus. Sixteenpatients were histologic responders, 1 partial-responder and 3 werenon-responders (Table 1 and 2). There was no difference in age, height,dose, or duration of therapy between the 16 histologic responders andthe 4 partial or non-responders. One partial-responder had received OVB0.5 mg/day; his highest count fell from 100 to 16 eos/hpf. The threenon-responders still demonstrated 50-80% improvement in their highestcounts with treatment (Tables 1 and 2). Of the 5 patients who werenon-responders to fluticasone proprionate, 3 were histologic responders,1 was a partial-responder and 1 was a non-responder to OVB therapy; thenon-responder still had a >70% drop in highest eosinophil count duringtreatment [Table 1].

Basal zone hyperplasia resolved completely in 6 of the 10 children withpan-esophageal findings. These patients were all histologic responders(Table 1).

Upper Gastrointestinal Endoscopy. Before treatment, the mean EEEndoscopy Score for all patients was 3.6 (range 1-6). The commonestfindings were pallor (90%), linear furrowing (80%) and white plaques(50%). Following treatment the mean EE Endoscopy Score was 0.8 (range0-5). The EE Endoscopy Score fell to 0 in twelve children and improvedin nineteen. Eleven with complete normalization were histologicresponders and 1 was a non-responder (>70% fall in eosinophil count).One child with an EE Endoscopy Scores that did not improve was ahistologic non-responder. (Tables 1, 2, 3).

Symptom Score. Before treatment the mean symptom score for all patientswas 4.4 and following treatment fell to 0.8 (p<0.0001). Eighteenchildren had an improved symptom score and 11 had a score of 0. Eight ofthese 11 patients were histologic responders with complete endoscopicresolution. Two children had symptom scores of 0 before and after OVBtherapy. Although these 2 children had symptom resolution on eliminationdiet or fluticasone, histologic resolution did not occur until aftertreatment with OVB. The 5 patients who took only PPI therapy prior tobudesonide did not have a significant improvement of symptoms onacid-suppression therapy alone (Tables 1, 2, 4).

There was a statistically significant correlation between the number ofeosinophils and the Endoscopy and Symptom scores (Spearman r of 0.64 and0.84 for the maximum eosinophil count and Symptom and Endoscopy score,respectively [p<0.0001]).

Discussion

Eosinophilic esophagitis is a disorder of the esophagus which isbecoming increasingly recognized (8, 14, 16, 17, 32-35). The annualincidence of the condition has been estimated at 1 in 10,000 children(35), but even this number may be an underestimate. The pathogenesis ofEE is still poorly understood; allergic and abnormal host immunologicresponses have been suggested. Therapeutic treatment options for EE haveincluded dietary restriction/elemental diet, systemic and topicalcorticosteroids(2, 22-30). There is, however, presently no topicalsteroid designed for esophageal drug therapy. Twice daily ingestedfluticasone propionate administered through an MDI is currently the mostwidely accepted topical therapy for EE. This therapy, however, may beparticularly problematic for younger children and those withdevelopmental delay who are unlikely to utilize the puff and swallowtechnique effectively (36). In this example, 10 of 13 children who wereunder the age of 5 and/or had developmental delay were responders to OVBtherapy. The 3 non-responders still demonstrated a 50-80% reduction inesophageal eosinophil count; all had symptomatic improvement and 2 hadendoscopic improvement. In addition to this, of the 5 children (ages 3-9yrs) who previously failed to respond to swallowed fluticasoneproprionate therapy, 3 had pan-esophageal histologic normalization withOVB and the other 2 had >75% reduction in esophageal eosinophil count.

These data suggest that following OVB therapy there is a strongcorrelation between the fall in esophageal eosinophil levels and theimprovement in the Endoscopy and Symptom Score. This suggests that thesescoring tools are useful clinical measures in pediatric EE but furtherprospective studies will need to be done in order to validate thesetools. Eighteen (90%) of the patients, including the partial-responderand one non-responder, had improved Endoscopy Scores and all symptomaticchildren had improved Symptom Scores. This may be because thepartial-responder and even the three non-responders had a 50-80%reduction in their highest esophageal eosinophil count following OVBtreatment. The correlation between the severity of symptoms and ofesophageal eosinophilic infiltration is not always so clear-cut. Twoinitially symptomatic children (#7 and 13, table 1) were asymptomaticbefore budesonide therapy despite having continued esophagealeosinophilic infiltration (80-120 eos/hpf). One child was a histologicnon-responder to elimination diet and the other to topical fluticasoneproprionate with PPI therapy, both for 3 months. These two childrenremained asymptomatic during budesonide therapy. This disassociationbetween symptoms and histologic disease is not unique to these two studypatients. In our practice we have treated adolescents who, havinginitially responded symptomatically and histologically to ingestedfluticasone proprionate, became non-compliant to therapy, claimed to beasymptomatic, but on routine follow-up evaluation had endoscopic andhistologic recurrence of disease. The exact reason for this remainsunclear. Children may become accustomed to their symptoms and notcomplain. Alternatively, they may conceal their symptoms because of anunwillingness to continue therapy or fear of undergoing further testssuch as endoscopy. Another possibility is that eosinophilic infiltrationmay not always cause symptoms, even within the same individual. Thiscould explain why some patients only complain of symptoms afteresophageal stricturing has occurred.

Most patients with EE are thought to have allergy-mediated disease,triggered by food and/or aeroallergens (2-4). However, 20% of the studypatients had no evidence of IgE-mediated sensitization to foods oraeroallergens, and this concurs with other reported estimates of EEoccurring in non-atopic individuals (17, 21, 35). Skin and patch testingcan suggest causative food allergens in over half of the patients withEE, but not all will respond symptomatically or histologically todietary restrictions (22). Amino-acid based formulas have been shown tobe effective (2, 24, 37), but many children find the formulanon-palatable and often require feeding through a naso-gastric orgastrostomy tube. In addition, after re-introducing new foods tochildren on elemental diets, patients require regular repeat UGIendoscopy to confirm continued control of inflammation. This exampleshows that children with EE, both with and without identifiablefood/aero allergies respond well to OVB therapy and most are able totolerate entirely normal diets. The dosing of OVB was based upon thetherapeutic recommendations for asthmatic children. Most of the patientsresponded to I mg daily, but two patients needed 2 mg a day before aresponse was seen. All patients tested, including those taking OVB 2 mgdaily, had normal morning cortisol levels and were therefore unlikely tohave significant adrenal suppression. This may be because budesonideabsorbed intestinally undergoes rapid hepatic metabolism.

Although there is conflicting data from pediatric and adult studies,with reports of negative 24 hr pH studies in children with EE, manypatients will have at least a partial symptomatic response toacid-suppression therapy (1, 7, 17, 30, 38). Acid-suppression therapyalone will not, however, significantly alter the histologic findings andpersisting esophageal eosinophilia may ultimately lead to esophagealnarrowing in 10-30% of cases (14, 18, 20, 21). This lack of histologicresponse to PPI therapy in patients with EE was confirmed in 10 of thestudy patients. Before starting all patients on OVB therapy, eosinophilswere more abundant and basal zone hyperplasia more prominent in distal,as compared with mid and proximal esophageal biopsies (80, 53 and 43eos/hpf, respectively for tissue eosinophils and 95%, 75% and 65% ofbiopsies for BZH, respectively). The reason for this distal-predominanceis unclear, but most likely supports the argument that GER does co-existwith EE, particularly as BZH and mild tissue eosinophilia also occur inreflux esophagitis. Therefore, all patients treated with OVB alsoreceived acid-suppression therapy.

These data suggest that oral viscous budesonide would be an effectiveand safe treatment for individuals, for example children, for example,young children, with proven EE. It may have advantages over othertherapies in that it is palatable, its volume (8-12 ml) providespan-esophageal mucosal coverage and it requires only once dailyadministration A larger placebo-controlled clinical trials would providemore information about dosing, efficacy and long-term safety of thistreatment.

Example 4

This example illustrates the increased interaction between a viscouscomposition described herein and the esophagus when compared to aradiolabeled oral composition made by combining Pulmicort Respules® (4mL) with ^(99m)Tc pertechnetate, and diluting with saline to about 7-8mL (MO). Administered to a population of healthy individuals was aradiolabeled oral viscous budesonide composition (M1), made in a volumeof about 7-8 mL by combining Pulmicort Respules®, about 10 packets ofSplenda®, and ^(99m)Tc pertechnetate, and comprises about 7% w/wmaltodextrin. The radiolabeled oral viscous budesonide composition (M2)was made in a volume of about 7-8 mL by combining Pulmicort Respules®,70% w/w maltodextrin, and ^(99m)Tc pertechnetate. Also administered to apopulation of healthy individuals was a radiolabeled oral non-viscousbudesonide composition. Increased interaction of the oral viscousbudesonide composition was determined by measuring the amount ofradiolabel present in the esophagus following oral administration of theoral viscous budesonide composition. FIG. 5 illustrates the percentamount of composition present in the esophagus as a function of timefollowing oral administration (by measuring the amount of radiolabelpresent in the esophagus).

The area under the curve (AUCr) of the percent of the dose administeredas a function of time (% dose·time(min)) was determined from the time of50% swallow (i.e., 50% of the administered dose had passed from themouth), until esophageal activity had peaked and fallen to 10% of thepeak value. The area under the curve from t=0 min to t=1 min (AUC₀₋₁);and from t=0 min to t=2 min (AUC₀₋₂) was also determined. These results(including the ratio of the non-viscous sample to the viscous sample)are set forth below:

AUCr AUC₀₋₁ AUC₀₋₂ geometric geometric geometric Formulation mean ratiomean ratio mean ratio M0 3.95 5.51 6.93 M1 6.33 0.62 8.84 0.62 9.41 0.74M2 17.67 0.22 18.91 0.29 21.94 0.32

Example 5

This example illustrates the reduced systemic affect of swallowing anoral composition described herein when compared to the administration ofan inhaled corticosteroid composition. Orally administered (byswallowing) was (1) a composition comprising 1 mg of budesonide (two 0.5mg/2 mL Pulmicort Respules®) and about 10 grams of maltodextrin (andminor amounts of other additives) (M4); and (2) a composition comprising1 mg of budesonide (two 0.5 mg/2 mL Pulmicort Respules®) diluted withwater to a volume of about 8-12 mL (M5). Administered by inhalation(using an LC Plus® nebuliser) was g 1 mg of budesonide (two 0.5 mg/2 mLPulmicort Respules®) (M6). As illustrated in FIG. 4, oral administrationof budesonide provided a significant decrease in AUC and Cmax valueswhen compared to the inhaled administration of dose of budesonide havingthe same nominal amount of budesonide.

TABLE 1 Patient characteristics pre- and post-viscous Budesonide(Budes.) therapy. Patient response was determined by counting thehighest eosinophil count/hpf after viscous budesonide and categorizedinto responders (0-7 eos/hpf), partial-responders (8-23 eos/hpf) andnon-responders (≧24 eos/hpf). Highest Eos. count/ Basel Zone Endos- PPIBudes Hpf Hyperplasia copy Symptom Age Prior** before Dose Pre/PostBudesonide (site*) Score Score Pt. mths. Res*** Sex ΔWt**** IGE* mths.Budes. mths. Site⁺ Pre Post Pre Post Pre Post Pre Post 1 42 R M −0.1 F,A ELIM No 1 mg M 70 1 Yes Yes 6 1 3 2 (4) (4) (P, M, D) (P, M) 2 33 R M0.15 X No 1 mg D 30 7 Yes Yes 1 0 7 3 (3) (D) (D) 3 71 R M 0.73 F, A Yes1 mg D 74 0 Yes No 2 0 5 0 (3) (P, D) 4 109 R M 0.85 X FLU Yes 1 mg M100 2 Yes No 4 2 4 0 (3) (4) (M, D) 5 41 R M −0.07 F, A ELIM Yes 1 mg D50 0 Yes No 2 1 8 3 (2) (3) (M, D) 6 66 M F, A FLU 1 mg P 60 50 6 1 4 3(3) (3) R M 0.5 F, A Yes 2 mg P 50 0 Yes No 1 0 3 2 (3) (M) 7 88 M F, AFLU Yes 1 mg D 50 80 4 4 0 0 (12)  (3) R 0.375 Yes 2 mg D 80 1 Yes No 40 0 0 (3) (P, M, D) 8 90 R F 0.63 X No 1 mg P 170 0 Yes No 6 1 9 0 (4)(P, D) 9 41 R M 0.18 A Yes 1 mg P, D 70 0, 0 Yes No 2 0 3 0 (4) (P, M,D) 10 20 R M 0.03 F Yes 1 mg D 80 0 Yes No 4 0 3 0 (4) (P, M, D) 11 201R F 0.1 A No 2 mg D 130 0 Yes No 6 0 5 1 (4) (P, M, D) 12 34 R M −0.15 XNo 1 mg D 100 0 Yes No 5 0 3 0 (3) (P, M, D) 13 51 R F 0.08 F ELIM No 1mg D 120 0 Yes No 2 0 0 0 (5) (6) (D) 14 48 R M 1.5 F ELIM No 1 mg D, M,P 30 0 Yes No 4 0 3 0 (5) (3) (P, M, D) 15 31 R M 0.2 F ELIM Yes 1 mg D100 5 Yes No 2 0 7 0 (3) (4) (P, D) 16 121 R M 0.13 F, A Yes 2 mg M 90 3Yes Yes 4 2 4 1 (3) (P, M, D) (P, M, D) 17 36 P M 0.46 F, A FLU No 0.5mg   D 100 16 Yes No 6 1 6 2 (12)  (3) (M, D) 18 32 N M 0.83 F No 1 mg D100 50 Yes Yes 2 3 3 1 (3) (M, D) (P, D) 19 68 N F 0.15 F ELIM Yes 1 mgD 100 28 Yes Yes 4 0 2 0 (2) (4) (P, M, D) (P, M, D) 20 93 N M 0.15 F, AFLU No 1 mg D 100 25 Yes Yes 5 2 8 0 (4) (P, M, D) (P, M, D) Patient 6and 7 failed treatment with 1 mg viscous budesonide, but responded to anincreased dose. Patient 11 was started on 2 mg viscous budesonidebecause of her age and size. Patient 16 had dose increased from 1 mg to2 mg viscous budesonide after one month because symptoms persisted onlower dose. *Specific IgE. Sensitization to food (F) or aeroallergens(A) as determined by RAST or skin-prick testing. X = none. **Priortherapy was with elimination diet (ELIM), topical fluticasoneproprionate and/or proton pump inhibitors (PPI). ⁺Site of esophagealinvolvement is divided into distal (D), mid (M), and proximal (P).***Response Category R = Responder, N = Non-Responder, P = PartialResponder. ****Weight change per month. mths = months. The highesteosinophil count/hpf, presence of basal zone hyperplasia, endoscopy andsymptom scores are given pre- and post-viscous budesonide therapy.Maximum Endoscopy score is 8 and maximum Symptom Score is 14.

TABLE 2 Esophageal eosinophil count pre- and post-viscous budesonide fordifferent patient response categories. Mean values and standard error ofmean (SEM) in parenthesis are provided for the highest esophagealeosinophil counts (eos/hpf) measured within the whole esophagus anddifferent sites. Esophagus Proximal Mid Distal Eos/hpf EsophagusEsophagus Esophagus Mean (SEM) Eso/hpf Eos/hpf Eos/hpf ResponseCatergory Pre Post Pre Post Pre Post Pre Post Responders  84    1.4** 44 1* 49  1**   75** 3 N = 16  (9)   (0.6) (11)   (0.5)  (8)   (0.5)  (8)(1) Partial-responder 100 20  50 20  60 ND 100 16  N = 1 Non-responders100 34* 50 6 68 19 100 34* N = 3  (0) (8) (25) (2) (17)  (4)  (0) (8) *p< 0.05 **p < 0.0001, Categories without asterisks do not reachstatistical significance.

TABLE 3 Eosinophilic esophagitis Endoscopy Scores, pre- and post-viscousbudesonide therapy, for different response categories. Total ScorePallor Furrows Plaques Esophageal Response Mean (SEM) Mean (SEM) Mean(SEM) Mean (SEM) Rings Category Pre Post Pre Post Pre Post Pre Post PrePost Responders 3.4 0.4** 1.4 0.3** 1.3 0.2** 0.8  0* None None N = 16(0.4) (0.2) (0.2) (0.2) (0.2) (0.1) (0.2) (0) Partial-responder 6 1 2 02 1 2 0 None None N = 1 Non-responder 3.7 1.7 1.7 0.7* 1 0.3 1   0.3None None N = 3 (0.9) (0.9) (0.3) (0.3) (0.6) (0.3) (0.6)   (0.3)Maximum total score is 8 and maximum for each category is 2. Standarderror of mean shown in parathesis. *p < 0.05 **p < 0.001, Categorieswithout asterisks do not reach statistical significance.

TABLE 4 Symptom Score, pre- and post-viscous budesonide therapy fordifferent response categories. Total Score Nocturnal Mean (SEM)Heartburn Pain Nausea/Vomiting Dysphagia Wakening Anorexia GI Bleed Cat.Pre Post Pre Post Pre Post Pre Post Pre Post Pre Post Pre Post Pre PostR 4.2 0.75** 1 0.1** 0.8   0.2* 1.4    0.1**   0.2   0.1 0.2 0 0.6 0.3None none N = 16 (0.6) (0.3) (0.2) (0.1) (0.2)   (0.1) (0.2)   (0.1)  (0.1) (1) (0.2) (0) (0.2) (0.2) P 6 2 2 1 2 1 2 0 0 0 0 0 0 0 NoneNone N = 1 N 5.5* 0.5* 1.5 0.5 1.5 0 1.5 0 1 0 0 0 0 0 None None N = 3(0.5) (0.5) (0.5) (0.5) (0.5) (0) (0.5) (0) (1) (0) Maximum total scoreis 14 and maximum for each category is 2. Standard error of mean shownin parenthesis. *p < 0.05 **p < 0.001, Categories without asterisks donot reach statiscal significance. Cat.: Response Category: R =Responders P = Partial-Responder, N = Non-Responders

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The entirety of each patent, patent application, publication anddocument referenced herein hereby is incorporated by reference. Citationof the above patents, patent applications, publications and documents isnot an admission that any of the foregoing is pertinent prior art, nordoes it constitute any admission as to the contents or date of thesepublications or documents.

Singular forms “a”, “an”, and “the” include plural reference unless thecontext clearly dictates otherwise. Thus, for example, reference to “asubset” includes a plurality of such subsets, reference to “a nucleicacid” includes one or more nucleic acids and equivalents thereof knownto those skilled in the art, and so forth. The term “or” is not meant tobe exclusive to one or the terms it designates. For example, as it isused in a phrase of the structure “A or B” may denote A alone, B alone,or both A and B.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meanings as commonly understood by one of ordinary skillin the art to which this invention belongs. Although any methods andsystems similar or equivalent to those described herein can be used inthe practice or testing of the present invention, the methods, devices,and materials are now described. All publications mentioned herein areincorporated herein by reference for the purpose of describing anddisclosing the processes, systems, and methodologies which are reportedin the publications which might be used in connection with theinvention. Nothing herein is to be construed as an admission that theinvention is not entitled to antedate such disclosure by virtue of priorinvention.

Modifications may be made to the foregoing without departing from thebasic aspects of the invention. Although the invention has beendescribed in substantial detail with reference to one or more specificembodiments, those of ordinary skill in the art will recognize thatchanges may be made to the embodiments specifically disclosed in thisapplication, and yet these modifications and improvements are within thescope and spirit of the invention. The invention illustrativelydescribed herein suitably may be practiced in the absence of anyelement(s) not specifically disclosed herein. Thus, for example, in eachinstance herein any of the terms “comprising”, “consisting essentiallyof”, and “consisting of” may be replaced with either of the other twoterms. Thus, the terms and expressions which have been employed are usedas terms of description and not of limitation, equivalents of thefeatures shown and described, or portions thereof, are not excluded, andit is recognized that various modifications are possible within thescope of the invention. Embodiments of the invention are set forth inthe following claims.

What is claimed is:
 1. A dissolving tablet, wherein said tablet containsa therapeutically effective amount of an active agent consisting ofbudesonide per tablet in combination with polyvinylpyrrolidone (PVP:povidone), wherein said tablet is formulated to rapidly dissolve in aspecific volume of liquid so as to generate a topical esophageal therapysuitable for reducing or alleviating esophageal inflammation or symptomsassociated therewith.
 2. The dissolving tablet of claim 1, wherein thevolume of liquid is from 5 to 50 mL.
 3. The dissolving tablet of claim2, wherein the volume of liquid is from 5 to 25 mL.
 4. The dissolvingtablet of claim 3, wherein the volume of liquid is from 5 to 15 mL. 5.The dissolving tablet of claim 1, wherein the liquid is water.
 6. Thedissolving tablet of claim 1, further comprising an excipient thatrenders the dissolving tablet palatable.
 7. The dissolving tablet ofclaim 1, further comprising at least one excipient that increasesviscosity of the topical esophageal therapy.
 8. The dissolving tablet ofclaim 7, wherein the topical esophageal therapy has a nectar-like tohoney-like viscosity.
 9. The dissolving tablet of claim 1, wherein theesophageal inflammation or symptoms associated therewith is associatedwith a disease or condition selected from the group consisting of:eosinophilic esophagitis, inflammatory bowel diseases involving theesophagus, Crohn's disease, esophageal inflammation secondary tocaustic/irritant ingestion, persistent/recurrent esophageal stricturesof any cause and including caustic/irritant ingestion, pill-inducedesophagitis, systemic diseases, congenital diseases, and post-surgeryinflammation.
 10. The dissolving tablet of claim 1, wherein the tabletis a wafer.
 11. A dissolving tablet comprising a therapeuticallyeffective amount of an active agent consisting of budesonide per tablet,wherein said tablet is formulated to rapidly dissolve in from 5 to 25 mLof liquid so as to generate a topical esophageal therapy suitable forreducing or alleviating esophageal inflammation or symptoms associatedtherewith, said tablet further comprising at least one excipient thatincreases viscosity of the topical esophageal therapy to a nectar-liketo honey-like viscosity.
 12. The tablet of claim 11, wherein said atleast one excipient that increases viscosity of the topical esophagealtherapy comprises lactose, sucrose, cellulose preparations, mannitol,sorbitol, honey, maize starch, wheat starch, rice starch, potato starch,gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethylcellulose,sodium carboxymethyl-cellulose (CMC), polyvinylpyrrolidone (PVP:povidone), or a combination thereof.
 13. The tablet of claim 1, furthercomprising a viscosity-enhancing excipient.
 14. The tablet of claim 13,wherein said viscosity-enhancing excipient is mannitol.
 15. The tabletof claim 1, further comprising a pharmaceutically acceptable salt. 16.The tablet of claim 15, wherein said pharmaceutically acceptable salt isselected from a group consisting of acetate, benzenesulfonate, besylate,benzoate, bicarbonate, bitartrate, bromide, calcium edetate, carnsylate,carbonate, citrate, edetate, edisylate, estolate, esylate, fumarate,gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate,hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide,isethionate, lactate, lactobionate, malate, maleate, mandelate,mesylate, mucate, napsylate, nitrate, pamoate (embonate), pantothenate,phosphate/diphosphate, polygalacturonate, salicylate, stearate,subacetate, succinate, sulfate, tannate, tartrate, teoclate, orcombinations thereof.
 17. The tablet of claim 16, wherein saidpharmaceutically acceptable salt is bicarbonate, carbonate, citrate, ora combination thereof.
 18. The tablet of claim 1, further comprising abuffering agent.
 19. The tablet of claim 18, wherein said bufferingagent is a citrate buffer.
 20. The tablet of claim 1, further comprisinga sweetener.